Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists

ABSTRACT

A compound of the following formula:  
                 
 
     and the salts thereof, wherein A is hydrogen, halo, hydroxy, or the like; the broken line represents an optional double bond with proviso that if the broken line is a double bond, then A is absent; Ar 1  is optionally substituted phenyl or the like; Ar 2  is aryl or heteroaryl selected from phenyl, napththyl, pyridyl, and the like, the aryl or heteroaryl being optionally substituted; R 1  is hydrogen, hydroxy, C 1 -C 4  alkyl, or the like; and R 2  and R 3  are independently selected from optionally substituted C 1 -C 7  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, and the like or R 2  and R 3 , together with the nitrogen atom to which they are attached, form an optionally substituted pyrrolidine, piperidine or morpholine ring. These compounds are useful as kappa agonists.

TECHNICAL FIELD

[0001] This invention relates to novel pyrrolidinyl and pyrrolinyl ethylan1ne compounds and their pharmaceutically acceptable salts, and to phanmaceutical compositions containing them. The pharmaceutically active compounds of this invention can be used as a selective kappa-receptor agonist.

BACKGROUND ART

[0002] Opioid analgesics such as morphine are therapeutically usewul, but their usage is strictly limited because of their side effects such as drug dependency and abuse. Thus, analgesics with high usefulness and reduced tendency to cause drug dependency are desired. Considerable pharmacological and biochemical studies have been carried out to discover the opioid peptides and opioid receptors, and the discovery of the subtype of opioid receptor such as mu (μ), delta (δ), kappa (k) in a variety of species, including human, has made a beginning towards creating new analgesics. As it is thought that opioid analgesics such as morphine act as a mu-receptor agonist, separating the action based on a kappa-receptor agonist from the action based on mu-receptor agonist has been investigated. Recently kappa-selective agonists (kappa-agonists) have been reported from the above viewpoint for example, EMD-61753: A- Barber et al, Br. J Phamacol., Vol. 113, pp. 1317-1327, 1994. Some of them actually have been studied in clinical trials (Med Res. Rev., Vol. 12, p. 525, 1992).

[0003] European Patent No. EP 0254545 B1 discloses a variety of ethylenediamine compounds. European Patent No. EP 0483580 A2 discloses a variety of pyrrolidine compounds as analgesics. International Publication WO 96/30339 discloses a wide variety of pyrrolidinyl hydroxamic acid compounds as selective kappa-receptor agonists

BRIEF DISCLOSURE OF THE INVENTION

[0004] The present invention provides a compound of the following formula:

[0005] and the salts thereof, wherein

[0006] A is hydrogen, halo, hydroxy, C₁-C₆ (preferably C₁-C₄) alktyl, halo C₁-C₆ (preferably C₁-C₄) alkyl, C₁-C₆ (preferably C₁-C₄) alkoxy, halo C₁-C₆ (preferably C₁-C₄) alkoxy, oxo, OY wherein Y is a hydroxy protecting group, or absent;

[0007] the broken line represents an optional double bond with proviso that if the broken line is a double bond, then A is absent;

[0008] Ar¹ is phenyt optionally substituted by one or more (preferably one to two) substituents selected from halo, hydroxys C₁-C₄ alkyl C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, CF₃, carboxy-C₁-C₄ alkoxy and C₁-C₄ alkoxy-carbonyl-C₁-C₄ alkoxy;

[0009] Ar² is aryl or heteroaryl selected from phenyl, naphthyl, pyridyl, thienyl, furyl, pyrrolyl and pyrimidyl, the aryl or heteroaryl being optionally substituted by one or more (preferably one to two) substituents selected from halo, hydroxy, amino, nitro, carboxv, C₁-C₄ alkyl C₁-C₄ alkoxy, C₁-C₄ alkylamino, di C₁-C₄ alkylamino, halo C₁-C₄ alkyl, C₁-C₄ alkythio and sulfonyt methyl;

[0010] R¹ is hydrogen, hydroxy, C₁-C₄ alkyt, C₁-C₄ alkoxy or OY wherein Y is a hydroxy protecting group; and

[0011] R² and R³ are independently selected from hydrogen, hydroxy, C₁-C₇ alkyl optionally substitted B or more (referablyono five) hydroxy or halo, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₇ (preferably C₁-C5) alkoxy, phenyl optionally substituted by halo (preferably substituted by one or two halogen atoms), phenyl C₁-C₇ (preferably C₁-C₅) alkyl, halo substituted phenyl C₁-C₇ alkyl, and (CH₂)nX-R⁴ wherein n is one or two, X is O, NH or S and R⁴ is C₁-C₃ alkyl, or when Ar² is phenyl, —Ar²—C(=C))—N(R2)— is a phthalimide group and R³ is C₁-C₇ alky, or

[0012] R² and R³, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by C₁-C₃ alkyl or halo.

[0013] When Ar² is phenyl, R²R³N—C(=O)— is preferably at the meta or para position on the phenyl ring with respect to 2—(A-pyrrolydinyl)-1-Ar¹-ethyl-N(R¹)—. When oxo is selected as “A” group, it is apparent that the oxygen atom should be attached to the pyrrolidinyli group through a double bond.

[0014] The pyrrolidinyl and pyrrolynyl ethylamine compounds of the present invention of formula (1) exhibit good kappa-receptor agonist activity, and thus are useful as an analgesic, anesthetic, anti-inflarnunatory or neuroprotective agent, and also usefil in the treatment of arthritis, stroke or functional bowel disease such as abdominal pain, for the treatment of a mammalian subject, especially a human subject. Specifically, these compounds are useful as an analgesic for acute and chronic pain. Especially, these compounds are useful as an analgesic at central nervous system in the mammalian subject. Also, these compounds are usefl as an analgesic for peripheral mediated inflammatory pain caused, for example by burns (induced by a contact with heat, acid or the other agents), scald (induced by a contact by hot liquid or steam), rheumatism or the like, in the said subject.

[0015] Accordingly, the present invention provides a pharmaceutical composition, which is useful as an analgesic, anesthetic, anti-inflammatory or neuroprotective agent, and also usefull in the treatment of the above-mentioned diseases, which comprises a therapeutically effective amount of the compound- of the formula (I), and a pharmaceutically inert carrier.

[0016] The present invention also provides a method for the treatment of a medical condition for which agonist activity toward opioid kappa-receptor is needed, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of the compound of the formula (I).

DETAILED DISCLOSURE OF THE INVENTION

[0017] In this speaification, the term “hydroxy protecting group” means a functional group to protect a hydroxy group against undesirable reactions during synthetic procedures, including, but not limited to benzyl, benzoyl, methoxymethyl, tetrahydropyranyl and trialkylsilyl.

[0018] The term “C₁-C₆ alkyl” is used herein means a straight or branched alkyl including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl and the like.

[0019] The term “C₁-C₄ alkoxy” is used herein to mean a straight or branched -OR (R is C₁-C₆ alkyl) including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, tert-butoxy and the like.

[0020] The term “halo” means F, Cl, Br or I, preferably F or Cl.

[0021] The term “halo C₁-C₆ alkyl” means a straight or branched, halo-substituted alkyl of 1 to 6 carbon atoms including, but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl and tert-butyl, substituted by I to 13 (preferably one to five) halogen atoms.

[0022] The term “halo C₁-C₆ alkoxy” means C₁-C₆ alkoxy substituted by 1 to 13 (preferably one to three) halogen atoms.

[0023] The term “halo substituted phenyl C₁-C₇ alkyl” means C₁-C₇ alkyl having a phenyl group attached to its terminal carbon atom, the phenyl group being substituted by one to five (preferably one to two) halogen atoms.

[0024] A preferred group of compounds of this invention includes the compounds of the formula (I) wherein

[0025] A is hydrogen, halo, hydroxy, oxo or OY; or if the broken line is a double bond then A is absent;

[0026] Ar¹ is phenyl optionally substituted by one to three substituents selected from halo, hydroxy, C₁-C₄ alkoxy, carboxy C₁-C₄ alkoxy and C₁-₄ alkoxy-carbonyl-C₁-C₄ alkoxy;

[0027] Ar² is phenyl, pyridyl or thienyl, optionally substituted by one to two halo or C₁-C₄ alkoxy,

[0028] R¹ is hydrogen, hydroxy or C₁-C₄ alkyl; and

[0029] R² and R³ are independently selected from hydrogen, C₁-C₇ alkyl optionally substituted by one or more hydroxy or halo, C₃-C₆ (preferably C₃-C₄) cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ (preferably C₂-C₃) allynyl, C₁-C₄ alkoxy phenyl and halo substituted phenyl C₁-C₇ alkyl, when Ar² is phengyl, —Ar²—C(=O)—NR²)— is a phthalimide group and R³ is C₁-C₇ alkyl, or

[0030] R² and R³, together with the nitrogen atom to which they are attached, form a pyrrolidine or morpholine ring.

[0031] A more preferred group of this invention includes the compounds of the formula (I) wherein

[0032] A is hydrogen, fluorine, chlorine, hydroxy or OY wherein Y is methoxymethyl or tetrahydropyranyt; or if the broken line is a double bond then A is absent or,

[0033] Ar¹ is phenyl optionally substituted by chlorine, hydroxy, methoxy or carboxymethoxy;

[0034] A² is phenyl, pyridyl or thienyl, optionally substituted by chlorine, fluorine or methoxy;

[0035] R¹ is C₁-C₄ alkyl;

[0036] R² is C₁-C₇ (preferably C₁-C₅) alkyl optionally substituted by hydroxy or fluorine, C₂-C₆ (preferably C₂-C₃) alkenyl, halo substituted phenylmethyl or phenyl; and

[0037] R³ is hydrogen or methyl; or

[0038] R² and R³ together with the nitrogen atom to which they are attached, form a pyrrolidine or morpholine ring.

[0039] A more preferred group of this invention includes the compounds of the formula (I) wherein

[0040] A is hydroxy, fluorine or chlorine; or if the broken line is a double bond, then Ak is absent; Ar¹ is phenyl optionally substituted by carboxymethoxy; Ar² is phenyl optionally substituted by methoxy or pyridyl; R¹ is C₁-C₄ alkyl; R² is C₁-C₇ alkyl optionally substitute by hydroxy; and R³ is hydrogen.

[0041] Preferred individual compounds are:

[0042] 4-{N-[2-(3-(S)-hydroxypyrroldin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide;

[0043] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-2- methoxy-N′-propylbenzamide;

[0044] 6{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyll-N-methylamino}-N′-propylnicotinamide;

[0045] 4-{-N-[1-(S-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)- ethyl]-N-methylamino}-N′-propylbenzamide;

[0046] 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide;

[0047] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamnide;

[0048] 5-{N-[2-(3 -(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylpicolinaide;

[0049] 4-{N-methylamino-N-[2-(3-pyrrolin-1-yl)-1-(S)-phenylethyl]}-N′-propylbenzamide; and

[0050] 4-{N-[2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamide.

[0051] Other preferre individual compounds are:

[0052] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-isopropylbenzamide;

[0053] 3-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide;

[0054] 2-chloro-4-{N-[2-(3-(S)-hydroxypyrroIidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide;

[0055] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-3-methoxy-N-propylbenzamide;

[0056] 3 -chloro-4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)-N′-propylbenzamide;

[0057] 4-{N-[1-(S)-(3-hydroxyphenyl)2-3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino)-N′-propylbenzamide;

[0058] 4-{N-[2-3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(3-methoxyphenyl)-ethyl]-N-methylamino}-N′-propylbenzamide;

[0059] 4- {N-[1-(S)phenyl-2-(pyrrolidin-1-yl)ethyl]-N-methylamino}-N′-propylbenzamide;

[0060] 4-{N-[1-(S)-(3 -chlorophenyl)-2-(3-(S)hydroxypyrrolidin-1-yl)-ethyl]-N-methylarino}-N′-propylbenzamide;

[0061] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(R)-phenyethyl]-N-methylamino}-N′-propylbenzamide;

[0062] 4-{N-[2-3-(S)hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-pyrrolidinebenzamide;

[0063] 4{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)phenylethyl]-N-methylamino}-morpholinebenzamide;

[0064] 4-{N-[2-(3-(S)hydroxypyrrolidin-1-yl)-1-(S)phenylethyl]-N-methylamino}-N′-(2-(R)hydroxypropyl)benzamide;

[0065] 4-{N-[2-3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-isobutylbenzamide;

[0066] 4-{N-(2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-allylbenzamide;

[0067] 4-(N-(2-3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(3,3,3,-trifluoropropyl)benzamide;

[0068] 3-fluoro4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide;

[0069] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2,2,3,3,3,-pentafluoropropyl)benzamide;

[0070] 4-{N-[2-3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-tert-amylbenzamide;

[0071] 5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylpicolinamide;

[0072] 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)-N′-(2-(S)-hydroxypropyl)benzamide;

[0073] 2-chloro-4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide; and

[0074] 4-{N-(2-3-(S)-chloropyrrotidin-1-y)-1-(S)-phenylethyll-N-methylarnino}-N′-propylbenzamide.

[0075] Other preferred compounds are:

[0076] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-methylbenzamide;

[0077] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-ethylbenzamide;

[0078] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenytethyl]-N-methylamino}-N′-butylbenzamide;

[0079] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-pentylbenzamide,

[0080] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-phenylbenzamide;

[0081] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-chlorobenzyl)benzamide;

[0082] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′,N′-dimethylbenzamide;

[0083] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-methyl-N′-propylbenzamide;

[0084] 5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propyl-2-thiophenecarboxamide;

[0085] 4-{N-[2-(3-(S)-hykoxyrpyrrolidin-1-yl)-1-(S)-phenylethyl]amino}-N′-propylbenzamide;

[0086] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylphthalimide;

[0087] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-ethoxybenzamide;

[0088] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino-N′-(3-hydroxypropyl)benzamide;

[0089] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylanino}-N′-cyclopropylbenzamide;

[0090] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(S)-sec-butylbenzamide;

[0091] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(R)-sec-butylbenzamide;

[0092] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propargylbenzamide;

[0093] 4-{N-[1-(R)-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide;

[0094] 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-tert-butylbenzamide;

[0095] 4-{(N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenytethyl]amino}-N′-propylbenzamide;

[0096] 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-hydroxyamino}-N′-propylbenzamide;

[0097] 4-{N-[2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide;

[0098] 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}-N′-propylbenzamide;

[0099] 4-{N-[2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(R)-hydroxypropyl)benzamide; and

[0100] 4-{N-[2-3-oxopyrroiidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide.

[0101] Further, the present invention provides a compound of the following formula:

[0102] wherein

[0103] Ar^(2a) is phenyl, pyridyl or thienyl,

[0104] X is hydrogen, halo or C₁-C₇ alkoxy;

[0105] R¹ is hydrogen, optionally protected hydroxy or C₁-C₄ alkyl; and

[0106] R² and R³ are independently hydrogen or C₁-C₇ alkyl optionally substituted hydroxy or halo.

[0107] Preferred individual compounds of the fornula (VId) are:

[0108] 4-methylamino-N′-propylbenzarsude;

[0109] 5-N-methylamino-N′-propylpicolinamide;

[0110] 2-chloro-4-methylarnino-N′-propylbenzamide;

[0111] 4-methylamino-N′-(2-(S)hydroxypropyl)benzamide;

[0112] 4-mnethylamino-N′-(2-(R)-hydroxypropyl)benzamide;

[0113] 4-methylamino-N′-(2,2,3,3,3-pentafluoropropyl)benzamide; and

[0114] 4-methylamino-N′-tert-amylbenzamide.

[0115] Further, the present invention provides compounds selected from

[0116] 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol,

[0117] 2-(3-(S)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol;

[0118] 2-(R)-phenyl-2-(3-pyrroline-1-yl)ethanol;

[0119] 2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol;

[0120] 2-(3-(R)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol;

[0121] 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylethanol;

[0122] 2-(3-(S)-fluoropyrrolidin-1-yl)-2-(S)-phenylethanol

[0123] 2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethanol; and

[0124] 2-(3-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol.

[0125] Further, the present invention provides processes for producing a compound of formula (I), which comprises reacting an anide compound of the formula (VId):

[0126] with an ethanol compound selected from compounds (Va), (Vb) and (Vc), and a mixture of compounds (Va) and (Vb):

[0127] in the absence or presence of a base in a reaction inert solvent.

[0128] General Synthesis

[0129] The kappa agonists (kappa-receptor agonists) of formula (I) of this invention can be prepared as described in the following schemes. Unless otherwise indicated, in the reaction schemes that follow, A, Ar¹, Ar², R¹, R² and R³ are defined as above.

[0130] Scheme 1a

[0131] In the above Scheme la, an optionally substituted styrene oxide (II) or an optionally substituted phenyl-1,2-ethanediol 2-tosylate (III) can be reacted with a pyrrolidine compound (IV) in the absence or presence of a base such as K₂CO₃ to form a mixture of substituted pyrrolidinyl ethanols (Va) and (Vb) This reaction may be carried out in the absence or presence of a reaction inert solvent (e.g., methanol (MeOH), ethanol (EtOH), isopropylalcohol, tetrahydrofuran (THF), dioxane, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride (CH₂Cl₂), water, benzene, toluene n-hexane or cyclohemne). This reaction can be carried out at a temperature from −78° C. to the reflux temperature of the solvent, preferably at from room temperature to a reflux temperature of the solvent for 5 minutes to 48 hours, preferably from 0.5 to 12 hours. The compound (Va) or the mixture of the compounds (Va) and (Vb), can be treated with methanesulfonyl chloride in the presence of a base such as triethylamine in a proper solvent such as dichloroethane, followed by coupling with a methyl ester compound of formula (VIa) to give an intermediate compound (VII). This coupling reaction can be carried out, in the absence or presence of a base such as sodium hydride (NaH), in a suitable polar solvent such as water, EtOH or DNS, at from room temperature to reflux temperature of the solvent, for 15 minutes to 6 hours.

[0132] Then, the intermediate compound (VII) may be treated with a base such as NaOH in a reaction inert solvent such as methanol, at a temperature from 0 to 100° C. for 5 minutes to 12 hours to give a carboxylic acid compound (VIM).

[0133] The carboxylic acid (VIII) cam be reacted with an alkyl arine in the presence of a carbodiiride compound to give the pyrrolydinyl ethylamine compound (I), A convenient carbodiimide compound is 1-ethyl-3-(3-dimeythylaminopropyl)carbodiimide (WSC). This reaction may be carried out by contacting substantially equivalent amounts of the carboxylic acid and alkylamine with a small exctss amount of the carbodiimide in an appropriate solvent Appropriate solvents are inert aromatic hydrocarbons, ethers, halogenated hydrocarbons, especially dichloromethane. The reaction may take place at a temperature in the range from −30 to 100° C., usually from 0 to 30° C. for 30 minutes to 74 hours, usually 12 to 16 hours at room temperature. The resulting product can be isolated and purified by standard techniques.

[0134] If required, the hydroxy protecting group in A of the compound (I) obtained (i.e., Y of —OY), can be removed by the appropriate method for the particular protecting, group chosen. For example, a typical protecting group methoxymethyl, can be removed by acid catalyzed hydrolysis in the presence of acid catalyst such as HCl A further convenient protecting group in A is the tetrahydropyranyl group (THP) This can be also removed by acid-catalyzed hydrolysis. Appropriate acid catalysts are organic acids, inorganic acids, or Lewis acids such as acetic acid (AcOH), ρ-toluenesulfonic acid (ρ-TsOH), hydrochloric acid (HCI), and dimethylaluminium chloride (Me₂AlCl). Preferred acid catalyst is HCl.

[0135] An optically inactive compound (I) wherein Ar¹ is optionally substituted phenyl, can be prepared by subjecting a corresponding optically inactive 1-phenyl-1,2-ethanediol 2-tosylate of the formula (III) or 1-phenyl-2-pyrrolidinylethanol (Vb) to the reactions described in Scheme 1a. Optically inactive compounds (IE), wherein Ar¹ is optionally substituted phenyl, may be prepared according to the procedures described in for example Tetrahedron, Vol. 47, pp. 9861-9866, 1991, Cehm. Rev., Vol. 80, pp. 187-213, 1980 or J. Org. Chem., Vol. 47, pp. 1229-1232, 1982, followed by tosylation such as reaction with ρ-toluanesulfonyl chloride in pyridine at 0° C. Optically inactive (Vb) can be prepared according to the procedures described for example in Tetrahedron Lett., Vol. 35, pp. 1511-1514, 1994 followed by a conventional reduction.

[0136] A compound of the formula (I) wherein A is hydroxy, R² is alkoxy and R³ is hydrogen; can be obtained from metylbenzoate of formula (VI) wherein A is hydroxy. First the hydroxy group of the methylbenzoate compound may be protected with a suitable protecting group such as tert-butyldimethysilyl group. Second the hydroxy-protected methyl ester compound can be subjected to hydrolysis to give the corresponding carboxylic acid. Then the carboxylic acid can be subjected to amidation to give the compound (M. The hydroxy protection can be conducted by subjecting the compound of the formula (VII) in DMF to a reaction with tert-butyldimethylsilytchloride and immidazole solution at about 0° C. for 1 to 6 hours. The hydrolysis can be carried out in the presence of a base such as sodium hydroxide in a polar solvent such as methanol at about the reflux temperature of the solvent for from 1 to 10 hours. The amidation can be carried out with a desired O-alkylhydroxylamine in the presence of a carbodiimide such as WSC at room temperature for from 1 to 24 hours. If deprotection is required, a conventional procedures can be employed. For example, when the hydroxy group is protected with tert-butyldimethylsilyl group, the amide compound can be treated with tetrabutylammonium fluoride in a proper solvent such as THF at room temperature.

[0137] A compound of formula (I), wherein A is absent and the broken line is a double bond, can be also prepared by subjecting a 2-phenyl-2-(3-pyrrolin-1-yl)ethanol compound (Vc) and a benzaairde compound to the coupling reactions illusrated in Scheme 1a.

[0138] The ethanol coompound (Vc) can be prepared by reacting a corresponding phenylglicinol and 1,4-dichlorobutene in the presence of base such as Et₃N in a reaction inert solvent such as ethanol at the reflux temperature of the solvent for 1 to 24 hours

[0139] A compound of the formula (1) wherein A is oxo (=O), can be prepared by oxidation of the corresponding pyrrolidinol compound. A suitable oxidation is Swern oxidation.

[0140] Further, the compounds of the formula (I) wherein —Ar²—C(=O)—N(R²)—, is a phthalimide group, can be prepared by using a compound of the formula (VIb):

[0141] instead of the compound (VIa) in the above-mentioned Scheme 1a.

[0142] Compounds of the formula (I) wherein Ar² is thienyl, can be prepared by using a methylaminothiophenecarboxamide of the formula (VIc):

[0143] instead of the compound (VIa)in the above-mentioned Scheme 1a. Compounds (VIc) can be prepared, first, by reacting a nitrothiophenecarboxaldehyde with the Jones reagent to give a nitrothiophenecarboxylic acid. Then, the carboxylic acid obtained can be subjected to condensation with a compound of the formula: NHR²R³, and then to reduction of the nitro group with iron powder and ammonium chloride, followed by methylation of the amino group.

[0144] The compounds of formula (II), (III) and (IV) are either known compounds, which can be made by the known methods, or they are analogs of known compounds, which can be prepared by methods analogous to the known methods.

[0145] According to the well known procedures or the following procedures, R, S configuration of compounds (Va) and (Vb) can be selectively determined by subjecting a 3-pyrrolidinol with the corresponding RS configuration.

[0146] Compounds of the fromula (Va) and (Vb) wherein A is fluorine and Ar¹ is phenyl, can be prepared from a commercially available 1-benzyl-3-pyrrolidinol. First, hydroxy group of the pyrrolidinol can be converted to an appropriate leaving group such as ρ-toluenesulfonate. The conversion can be achieved by subjecting the ptrrolidinol to the reaction with ρ-toluenesulfonyl chloride in pyridine. Second, the leaving group may be replaced by fluorine by a reaction with a suitable fluorinating agent such as tetrabutylamrnonium fluoride in a reaction inert solvent such as THF. Then, the 3-fluoropyrrolidine can be subjected to hydrogenation followed by a coupling with a stylene oxide of formula (II). The hydrogenation can be carried out in the presence of a suitable cat Ayst such as palladium hydroxide on carbon under hydrogen atmosphere in a reaction inert solvents such as EtOH at from 0° C. to a room temperature for 5 Minutes to 48 hours preferably 12 to 36 hours. The coupling reaction can take place in the absence or presence of a reaction inert solvent such as EtOH.

[0147] Compounds of the fromula (Va) and (Vb) wherein A is chlorine and Ar¹ is phenyl can aiso be prepared from 1-benz1-3-pyrrolidinoL For xmple, the 1-benzyl-3-pyrrolidinol can be subjected to chlorination to give 1-benzyl-3-chloropyrrolidine The benzyl group of the 1 -benzyl-3-chloropyrrolidine can be removed by treating the 1-benzyl-3-chloropyrrolidine with 1-chloroethyl chloroformate followed by coupling with styreneoxide of the formula (II). The chlorination 1-benzyl-3-pyrrolidinol can be carried out under a conventional condition, for example in the presence of a suitable reagent such as triphenylphosphine in a suitable solvent such as CCl₄ at room temperature. The debenzylation can be carried out accroding to the well known methods. The debenzylation is typically carried out In a reaction inert solvent such as dichloroethane at the reflux temperature of the solvent for 5 minutes to 3 hours. Then the solvent may be evapolated and the residue can be subjected to the coupling reaction with styrene oxide in a suitable solvent such as EtOH at the reflux temperature of the solvent for 5 minutes to 4 hours.

[0148] Compounds (Va) and (Vb) wherein A is halo and Ar¹ is a optionally substituted phenyl, can be prepared from a desired N-protected 3-pyrrolidinol compound via the corresponding N-protected 3-halopyrrolidine. First, 1-benzyl-3-pyrrolidinol can be treated with a suitable halogenation reagent in a reaction inert solvent for example, triphenylphosphine in CCl₄ at the reflux temperature of the solvent for from 3 to 36 hours. Second, the 1-benzyl-3-chloropyrrolidine can be purified, and deprotection can be carried out under conditions known to skilled in the art (e.g., with 1-chloroethyl chlorofornate in dichloroethane at 0° C. for 30 minutes to 6 hours). Third, the 3-chiloropyrrolidine can be treated with a styreneoxide compound to give the ethanols (Va) and (Vb) according to the procedures illustrated in Scheme 1a

[0149] Methyl ester compounds of the formula (VIa), wherein Ar² is optionally substituted phenyl, are known compounds or can be prepared by treating a substituted 4-aminobenzoic acid compound with an alkylhalide in the presence of a base such as NaH or Na₂CO₃ in a reaction inert solvent such as DMF.

[0150] More specifically, the compounds of the formula (Vla) can be prepared by the following methods.

[0151] A: Methyl 3-methylarninobenzoate of the formula (Vla) can be prepared by first subjecting 3-acetamidebenzoic acid to methylation in the presence of a base such as NaH in a reaction inert solvent such as DMF, followed by deacetylation in the presence of an acid catalyst such as conc. sulfuric acid (H₂SO₄).

[0152] B: A compound of the formula (Via) wherein Ar² is substituted by fluorine and R¹ is hydrogen, can be prepared from a nitrobtnzoic acid by subjecting the nitrobenzoic acid to esterification followed by reduction. The esterification can be achieved in the presence of acid catalyst such as sulfuiwc acid in MeOH at the refltux temperatwe of the solvent for 1 to 12 hours. The reduction can be carried out in the presence of a reducing agent such as iron powder in a suitable solvent such as acetic acid at from room temperature to 60° C. for 0.5 to 6 hours. If desired, the amino group can be alkylated by a well known method. For example, first the methyl ester can be treated with trifluoroacetic anhydride in the presence of base such as Na₂CO₃ in a suitable solvent such as CH₂Cl₂, then can be alkylated with a suitable alkylating agent such as iodomethane. A compound of the formula (VIa) wherein Ar² is substituted by chlorine and R¹ is alkyl, can be prepared from a chlorobenzoic acid by alkylation . The alkylation can be take place in the presence of a base such as NaH with a suitable alkyl halide in a reaction inert solvent such as DMF at about 0° C. for 1 to 24 hours.

[0153] C: A compound of the formula (VIa), wherein Ar² is pyridyl; the methylester group is on the 3-position and the R¹HN— is on the 6-position of the pyridine ring respectively, can be prepared by esterification of a 6-aminonicotic acid The crude residue of the methyl ester obtained may be subjected to methylation of the amino group. A suitable esterificating agent is, for example, trimethylsilyldiazomethane. The methylation of the amino group can be carried out according to the same procedures of the above mentioned preparation of compounds (VIa).

[0154] Alternatively, an amide compound of the general formula (VId)

[0155] wherein Ar^(2a), X, R¹, R² and R³ are defined as above, can be subjected to the coupling reaction with compounds (Va) and (Vb) to directly give a compound (I). This coupling reaction can be carried out in the absence or presence of a base such as NaH in a reaction inert solvent. The preferred solvents include EtOH and DMF. The reaction can be carried out at a temperature in the range of −78° C. to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature, for 5 minutes to 48 hours, preferably 0.5 to 24 hours.

[0156] The amide compounds of the formula (Vid) can be prepared according to the procedures described below.

[0157] A: A compound of the formula (VId) wherein Ar^(2a) is phenyl; R¹ is hydroxy and X is hydrogen, can be obtained by reduction of a known nitro N-alkylbenzmide compound. Suitable reducing. agents include for example, zinc powder. This reduction can be carried out by adding the reducin, agent to a mixture of the nitro N-alkylbenzarnide compound and ammonium chloride at about room temperature (e.g., 20-25° C.) for from 1 to 3 hours.

[0158] B: A compound of the formula (VId) wherein Ar^(2a) is phenyl; R¹ is hydrogen or C₁-C₄ alkyl; R² is C₁-C₇ alkyl optionally substituted by hydroxy; R³ is hydrogen and X is hydrogen or halo, may be prepared from a known amino benzoic acid compound, wherein the phenyl ring is optionally substituted by halo. The benzoic acid can be subjected to amidation under the similar conditions to those illustrated in Scheme 1a. If desired, the amino group of the benzamide compound obtained can be alkylated. For example, preferable alkylating agent is alkylhalide, and this alkylation can be carried out in the presence of base such as potassium carbonate at about room temperature for 12 to 24 hours.

[0159] C: An amide compound (Vld) wherein Ar^(2a) is pyridyl, and —NHR¹ group is on the 5-position and the amide group is on the 2-position of the pyridine ring respectively, can be prepared by treating an amino-protected picolinic acid with oxalyl chloride followed by amidation with an desired alkyl amine. The treatment of the 5-protected-amino picolic acid and oxalyl chloride can be performed in a reaction inert solvent such as CH₂Cl₂ or DMF/CH₂Cl₂ in the presence of a base such as triethylamine at room temperature. The arnidation can be carried out in the presence of a base in a reaction inert solvent. The base is preferably triethylaxine and the reaction may be conducted in a suitable solvent, e.g., dichloroethane at about 15° C. If required, the amino protecting group can be removed by the procedures known to those skilled in the art.

[0160] An alternative method to prepare the compounds of the formula (I) is illustrated in the following Scheme 1b.

[0161] Scheme 1b

[0162] The mixture of the compounds (Va) and (Vb) can be treated With methanesulfonyl chloride in a similar way as shown in Scheme 1a, followed by coupling with a cyano compound (VIe) to give the compound of the formula (VIIb). This coupling reaction can be carried out in a reaction inert solvent such as DMF or ethanol, in the presence or absence of base such as NaH, NaNH₂ or 2,6-lutidine. This reaction may take place at from room temperature to the reflux temperature of the solvent for 30 minutes to 12 hours.

[0163] Then, the compound (VIIb) may be reacted with a suitable alkoxide such as t-BuOK in the presence of water, in a polar solvent such as t-BuOH. This reaction may take place at reflux tem for 5 minutes to 6 hours. Then, a proper alkyl halide can be added to the resulting reaction rmixture. The mixture thus obtain,ed is refluxed for 5 minutes to 5 hours. The target compound (I) can be isolated and purified from a resulting reaction mixture by standard techniques.

[0164] Cyano compounds of the formula (Vie), wherein Ar² is a substituted phenyl can be prepared by treating known substituted 4-aminobenzonitrile compounds with NaH or K₂CO₃, followed by alkylation with an alkylhalide in a reaction inert solvent such as The compounds of formula (I) of this invention are basic, and therefore they will form acid-addition salts. All such salts are within the scope of this invention However, it is necessary to use an acid addition salts which is pharmaceutically-acceptable for administration to a mammal. The acid-addition salts can be prepared by standard methods, e.g., by contacting the basic and acidic compounds in substantially equivalent proportions in water or an organic solvent such as methanol or ethanol, or a mixture thereof. The salts can be isolated by evaporation of the solvent. Typical salts which can be formed are the hydrochloride. nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ρ-toluenesulfonate, oxalate and pamoate (1,1′-methylene-bis-(2-hydroxy-3-naphtoate)) salts.

[0165] The compounds of formula (I) of this invention, wherein Ar¹ is phenyl substituted by carboxy-C₁-C₄ alkoxy are acidic, and they will form base salts. All such salts are within the scope of this invention. However, it is necessary to use a base salt which is pharmaceutically-acceptable for administration to a mamnmal. The-base salts can be prepared by standard methodsl, e.g., by contacting the acidic and basic compounds in substantially equivalent proportions in water or an organic solver, such as methanol or ethanol, or a mixure thereof- The salts can be formed are the sodium, potassium, calcium and magnesium salts, and also salts with ammonia and amines, such as ethylamine, diethylamine, cyclohexylamine, piperidine or morpholine salts.

[0166] Also included within the scope of this invention are bioprecursors (also called as pro drugs) of the kappa agonist compounds of the formula (I). A bioprecursor of a kappa agonist of formula (I) is a chemical derivative thereof which is readily convened back into the parent compound of formula (I) in biological systems. In particular, a bioprecursor of a kappa agonist of formula (I) is converted back to the parent compound of formula (I) after e bioprocursor has been adjining to, and absorbed by, a mammalian subject, e.g., a human subject. For example, it is possible to make a bioprecursor of a kappa agonist of the invention of formula (I) in which one or both of A and R¹ is hydroxy groups by making an ester of the hydroxy group. When only one of A and R¹ is a hydroxy group, only mono-esters are possible. When both A and R¹ are hydroxy, mono- and di-esters (which can be the same or different) can be made. Typical esters are simple allanoate esters, such as acetate, propionote, butyrate, etc In addition, when A or R¹ is a hydroxy group, bioprecursors can be made by converting the hydroxy group to an acyloxytnethyl derivative (e. g., a pivaloyloxymethyl derivative) by reaction with an acyloxymethyl halide (e. g., pivaloyloxymethyl chloride).

[0167] The kappa agonists compounds of the present invention of formula (I) exhibit significant agonist activity toward opioid kappa-receptor and are thus useful as an analgesic, anesthetic, anti-inflammatory agent or neuroprotective agent, and also usefiul in the treatment of arthritis, stroke or functional bowel disease such as abdominal pain, for the treatment of a mammalian subject, especially a human subject.

[0168] The activity of the kappa-agonists compounds of formula (I) of the present invention, is demonstrated by the opioid receptor binding activity. Such activity mav be determined in homogenate from guinea pig whole brain, as described by Regina, A. et al., in J. Receptor Res., Vol. 12: pp. 171-180, 1992. In summary, tissue homogenate is incubated at 25° C. for 30 min in the presence of labelled ligand and test compounds The mu-sites are labelled by 1 nM of (3H)-D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), the delta-sites by 1 nM of (3H)-(D-Pen2,5]enkephalin (DPDPE) and the kappa-sites by 0.5 nM (3H)-CI-977. The non specific binding is measured by use of 1 μM CI-977 (kappa), IgM (DAMGO) (mu), 1 μM (DPDPE) (delta). Data are expressed as the IC₅₀ values obtained by a nonlinear fitting program using the Cheng and Prusoff equation. Some compounds prepared in the Examples showed a potent IC₅₀ value against kappa receptor in the range of 0.01 to 100 nM.

[0169] The analgesic activity of the kappa-agonist compounds at the central nervous system can also be demonstrated by the Formalii Test as described by Wheeler-Aceto, H. et al. in Psychopharmacology, Vol. 104: pp.35-44, 1991. In this testing, male SD rats (80-100 g) are injected s.c. with a test compound dissolved in 0.1% methyl cellulose saline or vehicle. After 30 min., 50 μl of a 2% formalin are injected into a hind paw The number of lickdng the injected paw per observation period is measured 15-30 min. after the injection of fbrmain and exp as % inhibition. compared to the respective vehicle group. Some compounds prepared in the Examples showed a potent ED₅₀ value in the range of less than 25 mg/kg p.o.

[0170] The activity of the kappa agonists, against peripheral acute-pain, can be demonstrated by the Randall-Selitto assay (M. E. Planas, Pain, Vol.60, pp. 67-71, 1995) In this testing, Male SD rats (100-120 g) were used and the nociceptive threshold at the right paw was measured by Randall-Selitto (Ugo Basile) method. After three days of acclimation of assay condition, experiments were carried out. Hyperalgesia was induced by the intraplantar injection of a 0.1 rml/right paw of 1% solution of carrageenin. Painful pressure were delivered to the right plantar via a wedge-shaped piston and the level of response were measured at 3.5 and 4.5 hr later the carrageenin injection. Some compounds, prepared in the working examples as described below, were tested in accordance with the above procedures, and showed good activity against acute-pain (i.e., ED₅₀ value of less than 10 mg/kg p.o.).

[0171] The activity of the kappa agonists, against chronic pain at the periphery, can be demonstrated by the adjuvant-induced hyperalgesia, according to the procedure described by Judith S. Waker el al., as reported in Life Sciences, Vol. 57, PP. 371-378, 1995. In this testing, male SD rats, weighing 180-230 g at the time of inoculation, were used. To produce adjuvant arthritis, rats were anesthetized with ether and inoculated intradernally into the footpad of the right hindpaw with 0.05 ml of Mycobacterium butyricum suspended in paraffin oil (2 mg/ml). Nociceptive threshold was evaluated by paw pressure test, using same procedures of the Randall-Selitto assay (as being described above), and edema was measured as the width of foot. Assays were done through the whole period.

[0172] The sedation function of kappa agonists can be determined by the Rotarod Tes; as described by Hayes, AG. et al. in Br. J. Pharmaco., Vol. 79, pp. 731-736, 1983 In this testing, a group of 6-10 male SD rats (100-120 g) are selected for their ability to balance on a rotating rod (diameter 9 cm, rate of rotation 5 r.p.m.). The selected rats are then injected s.c. with a test compound dissolved in 0.1% methyl cellulose saline The animals are tested again 30 min. after treatment; a rat falling off the bar more than twice within 150 seconds is considered to be showing motor impairment and the animal's performance (i.e., time on the rotarod) are recorded. The ED₅₀ value, defined as the dose of the drug which have the performance time is observed in the control group Some compouuds, prepared in the working example as described below, were tested in accordance with the above procedures.

[0173] The diuresis function of the kappa agonists can be determined according to the procedure described by A Barber et al., (Br. J. Pharmacol., Vol. III, pp. 843-851, 1994). Some compounds, prepared in the working examples as described below, were tested in accordance with the above procedures.

[0174] The kappa agonists compounds of formula (I) of this invention can be administered via either the oral, parenterat or topical routes to mammals. A preferable dosage level may be in a range of from 0.01 mg to 10 mg per kg of body weight per day, although variations will necessarily occur depending upon the weight and condition of the subject beitg tre,ard, tlj disease state being treated and the particular route of administration chosen. Hdwever, a dosage level that is in the range of from 0.01 mg to 1 mg per kg of body weight per day, single or divided dosage is most desirably employed in humans for the treatment of pain in a postoperative patient and a pain like hyperalgesia caused by chronic diseases.

[0175] The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, trochees, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oral pharmaceutical compositrons can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weight, preferably I0% to 50% by weight.

[0176] For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene grycols When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined wit various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifylng and/or suspending agents as wel, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

[0177] For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH>8) if necessary and tthe liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is also possible tb administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

EXAMPLES AND PREPARATIONS

[0178] The present invention is illustrated by the following examples and preparations. However, it should be understood that the invention is not lirted-to the specific details of these examples and preparations. Melting points were taken with a Buchi micro melting point apparatus and uncorrected. Infrared Ray absorption spectra (IR) were measured by a Shiradzu infrared spectrometer (IR-470). ¹H and ¹³C nuclear magnetic resonance spectra (NMR) were measured in CDCl₃ by a JEOL NMR spectrometer (JNM-GX270, 270MHz) unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad.

PREPARATION I

[0179] 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol

[0180] To a stirred solution of (S)(−)-1,2,4-butanetriol (10.61 g, 0.1 mol) in pyridine (50 ml) was added ρ-toluenesulfonyl chloride (38.13 g, 0.2 mmol) by portions at 0° C. After 14 h stirring, the reaction mixture was poured into conc. HCl aqueous solution including ice and acidified to pH2. The miture was exCLacted with ether (100 ml×3). The extract combined was washed with brine, dried (Na₂SO₄), and concentrated to give 18 58 g of colorless oil. To a stirred solution of this crude ditosylate (18 58 g, 45.7 mmol) and dimethoxym m (50 ml) in CH₂Cl₂(50 ml) was added P₂O₅ by portions at rt (room temperature) and stirred for 26 h. The CH₂Cl₂ layer was separated and the P₂O₅ (50 g) solid was wasr with CH₂Cl₂ (50 ml×4). The CH₂Cl₂ layer combined was washed with saturated NaHCO₃ aqueous solution and brine. After dry (Na₂SO₄), the solvent was evaporated to afford 18.01 g of brown viscous oil. A mixture of this oil (18.00 g,40 mol), K-(−) 7-phonylglycin 1(14.80, 35 mm l), and Et₃N (11.3 ml, 80 mmol) in ethanol (20 ml) was refluxed with stirring for 81. The solvent was evaporated and the residue was dissolved in CH₂Cl₂ (200 ml). This solution was washed with saturated NaHCO₃ aqueous solution and brine, dried (Na₂SO₄), and concentrated to give 16.69 g of brown viscous oil, which was purified by column chromatography (silica gel 200 g, CH₂Cl₂/MeO(H:20/I) to afford 5.13 g (20.4%, over all yield) of clear brown viscous oil. ¹H NMR (270MHz, CDCl₃) δ7.40-7.25 (5H, m), 4.62 (1H, d, J=7.0Hz), 4 58(1H, d, J=7.0Hz), 425-4.15 (1H, m), 3.88 (1H, dd, J=5.9, 10.6Hz), 3.80 (1H, dd, J=59, 10 6Hz), 3.50 (1H, t, J=5.9Hz), 3.33 (3H, s), 2.76 (1H, dt, J=6.2, 8.4Hz), 2.71 (1H, dd, J=5.9, 10.3Hz), 2.63 (1H, dd, J=3.3, 10.3Hz), 2.45 (1H, dt, J=6.2, 81Hz), 2.18 (1H, br s), 2.16-2.02 (1H, m), 1.87-1.75 (1H, m). IR(neat): 3450 cm⁻¹.

Preparation 2

[0181] 2-(3-(S)-Methoxnmethoxpyrrolidin-1-yl)-1-(S)phenylethanol and 2-(3-(S)-Methoxymethoxyprrolidin-1-yl-2-R)-phenylethanol

[0182] A mixture of 3-(S)-methoxymethoxypyrrolidine (4.37 g, 33.3 mmol) and (S)-(−)-styrene oxide (4.00 g, 33.3 mmol) in EtOH (40 ml) was refluxed with stirring for 2 h. After evaporation of the solvent, the residue was purified by column chromatography (slicagel: 120 g, CH₂Cl₂:MeOH=40:1-20:1) to give 4.91 g (58.7%) of pale yellow oil as 0.65 to 0.35 mixture of title compounds.

[0183]¹HNMR (270MHz, CDCl₃) δ7.40-7.27 (5H, m), 4.68-4.63 (2.65H, m), 4.35-4.15 (1H, m), 3.90-3.75 (0.7H, m), 3.49 (0.35H, t, J=5.9Hz), 3.38 (1.95H,s), 3.32 (1 05H, 3), 3.10-2.90 (1.3H, m), 2.80-2.40 (4H, m), 2.20-2.00 (1H, in), 1.95-1.75 (2H, m)

Preparation 3

[0184] 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol

[0185] A mixture of 3-(S)-methoxyrnethoxypyrrolidine (6.10 g, 46.5 mmol), (S)-(+)-1-phenyl-1,2-ethanediol-2-tosylate (13.6 g, 46.5 mmol) and K₂CO₃ (7.06 g, 51.1 mmol) in EtOH (80 ml) was refluxed with stirring for 4.5 h. After evaporation of the solvent, CH₂Cl₂ was added tothe residue and washed with saturated NaHCO₃ aqueous solution, brine, dried (Na₂SO₄), and concentrated to give 14.94 g of crude products, which was purified by colurmn chromatography (slicagel: 150 g, CH₂Cl₂/MeOH=50:1-20:1) to afford 7.75 g (66.4%) of brown oil as 0.65 to 0.35 mixture of title compounds.

[0186]¹H NMR (270MHz CDCl₃) 7.40-7.27 (5H, m), 4.68-4.63 (2.65H, m), 4.35-4.15 (1R, m), 3.90-3.75 (0.7H, m), 3.49 (0.35K, t, J=5.9Hz), 3.38 (1.95H,s), 3.32 (1.05H, s), 3.10-2.90 (1.3H, m), 2.80-2.40 (4H, m), 2.20-2.00 (IH, m), 1.95-1.75 (2H, m)

Preparation 4

[0187] 2-R)-Phenyl-2-(3-(S)-tetrahydropyran-2-yloxyrrolidin-1-yl)ethanol and 1-(S)-Phenyl-2-(3-(S)-tetrahydropyran-2-yloxyprrolidin-1-yl)ethanol

[0188] This was prepared from 3-(S)-tetrahydropyranyloxypyrrolidine (300 g, 17.5 mmol) and (S)-(−)-styrene oxide (2.10 g, 17.5 mmol) in 50% yield as 0.35 to 0.65 mixture of title compounds according to a procedure similar to that described in Preparation 2.

[0189]¹H NMR (270MHz, CDCl₃) δ7.50-7.20 (5EI, m), 4.71 (0.65H, dd, J=3.3, 10 6Hz), 4.6-4.50 (1H, m), 4.45-4.25 (1H, m), 3.95-3.75 (1.7H, m), 3.60- 3.42 (1.35H, m), 3.20-2.40 (5.3H, m), 2.25-1.45 (9H, m).

Preparation 5

[0190] 2-(R)-Phenyl-2-pyrrolidin-1-yl-ethanol and 1-(S)-Phenyl-2-pyrrolidin-1-yl-ethanol

[0191] This was prepared from pyrrolidine (592 m, 8.32 mmol) and (S)-(−)-styrene oxide (1.00 g, 8.32 mmol) in 96% yleld as 0.3 to 0.7 mixture of title compounds according to a procedure sinilar to that described in Preparation 2.

[0192]¹H NMR (270MHz, CDCl₃) δ7.45-7.27 (5H, m), 4.70 (0.7H, dd, J=3.3, 10 6Hz), 3 87 (0.3H, dd, J=5.9, 10.6Hz), 3.81(0.3H, dd, J=5.9, 10.6Hz), 3.47 (0.3H, t, J=5.9Hz), 2.90-2.70 (1.4H, m), 2.65-2.40 (4H, m), 1.90-1.60(5H, m).

Preparation 6

[0193] Methyl 3-methoxy-4-methylaminobenzoate

[0194] To a suspension of NaH (2.43 g, 60.7 mm DIMF (20 ml) was added a solution of 4-amino-3-hydroxybenzoic acid (3.00 g, 19.6 mmol) in MF(20 ml) at 0° C. After stirring at room temperature for IH, iodomethane (3.78 ml, 60.7 mmol) was added to this mixture at 0° C. and stirred at room temperature for 16 h. The mixture was poured into ice water and extracted with nHex:AcOEt:Et₂O=1:1:1 (300 ml). The extract was washed with water, bdnnc dried (Na₂SO₄), and concentrated to give brown oil, which was purified by column chromato-graphy (silica gel 190 g, nHex/AcOEt=10/1 and silica gel 35 g, CH₂Cl₂ only) to afford 481 mg (13%) of title compound.

[0195]¹H NMR (270MHz, CDCl₃) δ7.66 (1H, dd, J=1.8, 8.4Hz), 7.40 (1H, d, J=1 8Hz), 6.52 (1H, d, J=8.4Hz), 4.72 (1H, br. s), 3.89 (3H, s), 3.86 (3H, s), 2.91 (3H, d, J=5.1 Hz)

Preparation 7

[0196] Methyl 2-methoxy-4-methylaminobenzoate

[0197] This was prepared from 4-amino-2-hydroxybenzoic acid (3.00 g, 19.6 mmol) in 22% yleld according to a procedure similar to that described in Preparation 6.

[0198]¹H NM (270MHZ, CDCl₃) δ7.77 (1H, d, J=8.8Hz), 6.16 (1H, dd, J=2.2, 8.8Hz), 6 08 (1H, d, J=1.8Hz), 4.19 (1H, br. s), 3.88 (3H, s), 3.82 (3H, s), 2.89 (3H, d, J=5.1 Hz).

Preparation 8

[0199] Methyl 2-chloro-4-methylaminobenzoate

[0200] This was prepared from 4-amino-2-chlorobenzoic acid (2.00 g, 11.7 mmol) in 13% yield according to a procedure similar to that described in Preparation 6.

[0201]¹H NMR (270MHz, CDCl₃) δ7.80 (1H, d, J=8.8Hz), 6.59 (1H, d, J=2.6Hz), 6.44 (1H, dd, J=2.6, 8.8Hz), 4.21 (1H, br. s), 3.86 (3H, s), 2.87 (3H, d, J=5.1 Hz).

Preparaiion 2

[0202] 3 -Chloro4-methylaminobenzonitrile

[0203] This was prepared from 4-amino-3-chlorobenzonitride (2.00 g, 13.1 mmol) in 42% yleld according to a procedure similar to that described in Preparation 6.

[0204]¹H NMR (270Mz CDCl₃) δ7.50 (1H, d, J=1.8Hz), 7.43 (1H, dd, J=1.8, 8.4Hz), 6.61 (1H, d, J=8.4Hz),4.92 (1H, br. s), 2.96 (3H, d, J=5.1Hz).

Preparation 10

[0205] Methyl 6-methylaminonicotinate

[0206] To a suspension of 6-aminonicotinic acid (1.00 g, 7.24 mmol) in MeOH (20 mol) and MeCN (10 ml) was added 10% solution of trimnethylsilyldiazoti.ethane in CH₂Cl₂ (25 ml) at room temperature. After stirring at room temperature for 0.5 h, the solvent was evaporated to give crude methyl 6-aminonicotinate as a yellow soiid. Title compound was prepared from this crude methyl 6-aminonicotinate in 17% yield according to a procedure similar to that described in Preparation 6.

[0207]¹H NNR (270Mz, CDCl₃) δ8.75(1H, d, J=2.2Hz), 8.01(1H, dd, J=2.2, 8 8Hz); 6.36(13, d, J=9.2Hz), 5.11 (1H, br. s), 3.87(3H, s), 2.99(3H, d, J=5.5Hz).

Preparation 11

[0208] Methyl 3-methyiaminobenzoate

[0209] To a suspension of NaH (1.54 g, 38.5 mmol) in DMF (20 ml) was added a solution of 3-acetamidebenzoic acid (3.00 g, 16.7 mmol) in DMF (20 ml) at 0° C. After stirring at room te ple for 0.5 h, iodomethane (2.40 ml, 38.5 mmol) was added to this mixture at 0° C. and stirred at room temperature for 1.5 h. The mixture was poured into ice 6N-HCl aqueous solution and extracted with AcOEt : toluene =2:1 (200 ml×3). The extract was washed with water, brine, dried (Na₂SO₄), and concentrated to give 3.08 g of brown oil. A mixture of this brown oil and cH₂SO₄ (5 ml) in MeOH (30 ml) was refluxed with stirring for 7 h. After cooling down to room temperature, the solvent was evaporated. The residue was basified with saturated NaHCO₃ aqueous solution and extracted with CH₂Cl₂. The extracted was washed with water, brine, dried (Na₂SO₄), and concentrated to give 2.3 μg (84%) of brown oil.

[0210]¹H NMR (270MHz, CDCl₃) δ7.37 (1, dt, J-1.4, 7.5Hz), 7.28-7.20 (2H, m), 6.78 (1H, ddd, J=0.75, 2.6, 8.1Hz), 3.89 (3H, s), 2.87 (3H, s).

Preparation 12

[0211] 4-Amino-N′-propylphalimide

[0212] To a suspension of NaH (493 g, 12.3 mmol) in DMF (10 ml) was added a solution of 4-aminophthalimide (2.00 g. 12.3 mmol) in DMF (10ml) at 0° C. After stirring at room temperature for 1 h, iodopropane (1.20 ml, 12.3 mmol) was added to this mixture at 0° C. and stirred at room temperature for 28 h. The mixture was poured into water and emacted with AcOEt:toluene=2:1(150 ml×3). The extract was washed with water, brine, dried (Na₂SO₄), and concentrated to give yellow solid, which was purified by column chromatography (silica gel: 130 g, CH₂Cl₂ only to CH₂Cl₂/MeOH=75/1) to give 1.14 g (45%) of yellow solid.

[0213]¹H NMR (270MHz, CDCl₃) δ7.59 (1H, d, J=8.1Hz), 7.03 (1H, d, J=2.2Hz), 6.81 (1H, dd, J=2.2, 8.1Hz), 4.32 (2H, br. s), 3.65-3.55 (2H, m), 1.80-1.60 (2H, m), 0.93(3H,t, J=7.3Hz).

Preparation 13

[0214] 4-Methylamino-N′-propylphthalimide

[0215] This was prepared from 4-amino-N′-propylphthalimide in 11% yleld according to a procedure similar to that described in Preparation 12.

[0216]¹H HNMR (270MHz, CDCl₃) δ7.59 (1H, d, J=8.4Hz), 6.96 (1H, d, J=2.2Hz), 6.71 (1H, dd, J=2.2, 8.4Hz), 4.50 (1H, br. s), 3.65-3.55 (2H, m), 2.95 (3H, d, J=5.1Hz), 1.80-1.60 (2H, m), 0.93 (3H,t, J=7.3Hz).

Preparation 14

[0217] 5-Nitro-2-thiophenecarboxylic acid

[0218] To a solution of 5-nitro-2-thiophenecarboxaldehyde (1.00 g, 6.24 mmol) in acetone (50 ml) was added Jones reagent (8N in acetone, 8.12 ml, 65 mmol) at −20° C. After stirring for 1H, 30 ml of isopropanol was added to the mixture. H₂O was added to the mixture and exacted with CH₂Cl₂. The extract was washed with water, brine, dried (Na₂SO₄), and concentrated to give 967 mg (90%) of yellow amorphous.

[0219]¹H NM(270MHz, CDCl₃) δ7.88 (1H, d, J=4.4Hz), 7.66 (1H, d, J=4.0Hz), 5.14 (1H, br. s).

Preparation 15

[0220] 5-Nitro-N-propyl-2-thiophenecarboxamide

[0221] To a solution of 5-nitro-2-thiophenecarboxylic acid (967 mg, 5.59 mmol) in DMF (0.745 ml) and CH₂Cl₂ (4 ml) was added oxalyl chloride at 0° C. After stirring for 0.5 h at rt (room temperature), the solvent was evaporated below 30° C. to give yellow oil and solid. To a solution of n-propylamine (0 551 ml, 6.71 mmol) in Et₃N (1 87 ml, 13.4 mmol) and CH₂Cl₂ (25 ml) was added a solution of crude acid chloride in CH₂Cl₂ (10 ml) below 20° C. After stirring for 4 h at rt, the mixture was washed with water, saturated NaHCO₃ aqueous solution. water, brine. dried (Na₂SO₄), and concentrated to give brown solid, which was purified by column chromatography (silica gel 50 g, CH₂Cl₂/MeOH=100/1-30/1) to afford 815 mg (68%) of white solid.

[0222]¹H NMR (270MHz, CDCl₃) δ7 85 (1H, d, J=40Hz), 7 35 (1H, d, J=4.4Hz), 6.12 (1H, br s), 3.50-3.35 (2H, m), 1.75-1.55 (2H, m), 0 99 (3H,t, J=7 3Hz)

Preparation 16

[0223] 5-Amino-N′-propyl-2-thiophenecarboxamide

[0224] A mixture of 5-nitroN-propyl-2-thiophenecarboxartide (815 mg, 3.81 mmol), iron powder (1.06 g, 19.0 mmol) and NH₄Cl (102 mg, 1.90 mmol) in EtOH (12 ml) and H_(2l O ()6 ml) was refiuxed with stirring for 2 h. The reaction mixture was filtered and washed with EtOH. The combined filtrate was evaporated. The residue was dissolved in AcOEt and washed with water, brine, dried (Na₂SO₄), and concentrated to give brown amorphous, which was purified by column chromatography (silica gel 40 g, CH₂Cl₂/MeOH=40/l) to afford 411 mg (59%) of brown amorphous.

[0225]¹H NMR (270MHZ, CDCl₃) δ7.09 (1H, d, J=3.7Hz), 6.07 (1H, d, J=4.0Hz), 5.80-5.60 (1H, m), 4 14 (2H, br. s), 3.40-3.25 (2H, m), 1.70-1.50 (2H, m), 0 96 (3H,t, J=7.3Hz)

Preparation 17

[0226] 5-Methylamino-N′-proply-2-thioohenecarboxamide

[0227] To a solution of 5-amino-N′-propyl-2-thiophenecarboxamide (411 mg, 2.23 mmol) in CH₂Cl₂(12 ml) was added Na₂CO₃ (710 mg, 6.70 mmol) and trifluoroacetic anhydride (0.63 ml, 4.47 mmol) at rt. After stirring for 5 h, the solid was filtered off The filtrate was washed with water and brine, dried (Na₂SO₄) and concentrated to give 396 mg of yellow oil. To a solution of this oil in DMF (6.5 ml) was added Na₂CO₃ (2.35 g, 22.2 mmol) and iodomethane (2.90 ml, 46.6 mmol) at rt. After stirring for 22 h. the mixture was poured into ice IN-HCI and extracted with AcOEt:toluene=2 1 The extract was washed with water, brine, dried(Na₂SO₄), and concentrated to give 298 mg of orange solid. To a solution of this solid in MeOH (3.5 ml) was added 7% K₂CO₃ aqueous solution (1.8 ml) at rt. After stirring for 18 h, the solvent was evaporated. The residue was dissolved in AcOEt and water. I he organic layer was washed with water, brine, dried (Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography(silica gel 15 g, CH₂Cl₂/MeOH=60/1-40/l) to afford 122.5 mg (44%) of title compound.

[0228]¹H NMR (270MHz, CDCl₃) δ7.16 (1H, d, J=4.0Hz), 5.89 (1H, d, J=4.4Hz), 5.68 (1H, br. s), 4.32 (1H, br. s), 3.40-3.30 (2H, m), 2.91 (3H, d, J=5.1Hz), 1.70-1.50 (2H, m), 0.96 (3H,t, J=7.3Hz).

Preparation 18

[0229] (S)-1-(3-Methoxymethoxyphenyl)-1.2-ethanediol

[0230] A mixture of 3-methoxymethoxystyrene (prepared by methoxymethylation of 3-hydroxystyrene in a standard manner) (1.54 g, 9.39 mmol), and AD-mix-α (13.18 g, 9.41 mmol) in water (48 ml) and t-BuOH (48rmi) was stirred at 0° C. for 6.5 h. To this reaction mixture was added Na₂SO₃ (14.13 g) and the mixture was stirred at rt for 1H The reaction miure was extracted with ethyl acetate. The extract was washed with brine, dried (Na₂SO₄), and concentrated to give light brown oil, which was purified by column chromatography (silica gel: 90 g, ethyl acetate/hexane:½-{fraction (3/1)}) to afford 1.69 g (91%) of desired product as colorless oil.

[0231]¹H NM (270MHz CDCl₃) δ7.25 (1H, dd, J=7.7, 8.1Hz), 7.03 (1H, d, J=1.8Hz), 6.98-6.92 (2H, m), 5.15 (2H, s), 4.74 (lH, dd, J=3.3, 8.1Hz), 3.71 (1H, br.d, J=9 9Hz), 3.65-3.55 (2H m, including 1H, dd, J=8.1, 11.0 Hz at 3.61 ppm, CHCH₂OH), 3.44 (3H, s), 3.14 (1H, br.s, OH).

Preparation 19

[0232] (S)-1-(3-Methoxymethoxyphenyl)-1.2-ethanediol-2-tosylate

[0233] To a stirred solution of (S)-1-(3-methoxymethoxyphenyl)-1,2-ethanediol (1.69 g, 8.54 mmol) in pyridine (20 ml) was added p-toluenesulfonyl chloride (1.63 g, 8.54 mmol) and 4-dimethylaminopyridine (1.04 g, 8.54 mmol) at 0° C. and the reaction mixture was stirred at 0° C. to rt for 16 h at 60° C. for 1 h. The reaction mixture was acidified with 2N HCl aqueous solution and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel: 150 g, ethyl acetatelhexane:½ to {fraction (2/1)}) to afford 2 01 (67%) of desired product as colorless oil Its optical purity was 98% ee by HPLC.

[0234]¹H NM (270MHz, CDCl₃) δ7.77 (2H, d, J=8.4Hz), 7.34 (2H, d, J=8. lHz), 7.25 (1H dd, J=7.7, 8.4Hz), 7.00-6.92 (3H, m), 5.15 (2K, s), 4.95 (1H, ddd, J=3.3, 3.3, 8.4Hz), 4.15 (1H, dd, J=3.3, 10.3Hz), 4.03 (1H, dd, J=8.4, 10.3Hz), 3 46 (3H, s), 2 65 (1H, d, J=3.3Hz), 2.45 (3H, s).

Preparation 20

[0235] 2-(R)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol

[0236] This was prepared from (S)-1-(3-methoxyrnethyloxyphenyl)-1,2-ethanediol-2-tosylate in 79% yleld as 0.25 to 0.75 rnixture of title compounds according to a procedure similar to that described in Preparation 3.

[0237]¹H NMR (270MHz CDCl₃) δ7.29-7.21 (1H, m), 7.09-6.91 (3H, m), 5.22-5.13 (2H, m), 4.80-4.55 (2.75H, m), 4.33-4.15 (1K m), 3.90-3.72 (0.5H, m), 3.51-3.45 (0.25H, m), 3.48 (3H, s), 3.38 (2.25H, s), 3.33 (0.75H, s), 3.05-2.90 (1.5H, m), 2.80-2.43 (4H, m), 2.23-2.02 (1EL m), 1.95-1.70 (2H, m).

Preparation 21

[0238] (S)-1-(3-Chlorophenyl)-1,2-ethanediol

[0239] This was prepared from 3-chlorostyrene in 100% yleld according to a procedure similar to that described in Preparation 18.

[0240]¹H NMR(270MHz, CDCl₃) δ7.40-7.20(4H, m), 4.90-4.75 (1H, m), 3.85-3 75 (1H, m), 3.75-3.60 (1H, m), 2.66 (1H, d, J=2.9Hz), 2.20-2.05 (1H, m).

Preparation 22

[0241] (S)-1-(3-Chlorophenyl)-1,2-ethanediol-2-tosylate

[0242] This was prepared from (S)-1-(3-chlorophenyl)-1,2-ethanediol in 74% yield according to a procedure similar to that described in Preparation 19. Its optical purity was 98% ee by HPLC.

[0243]¹H NM (270MHz, CDCl₃) δ7.76 (2H, d, J=8.1Hz), 7.32 (2H, d, J=8.4Hz), 7.31-7.17 (4H, m), 5.00-4.92 (1H, m), 4.14 (1H, dd, J=3.3, 10.6Hz), 4.02 (1H, dd, J=8.4, 10.6Hz), 2.63 (1H, d, J=3.7Hz), 2.46 (3H, s).

Preparation 23

[0244] 2-(R)-(3 -Chlorophenyl)-2-(3-(S)-methoxytethoxypyrrolidin-1-yl)ethanol and 1-(S)-(3-Chlorophenyl)-2-(3-(S)-methoxymethoxyrrolidin-1-yl)ethanol

[0245] This was prepared from (S)1-(3-chlorophenyl)-1,2-ethanediol-2-tosylate in 62% yleld as 0.15 to 0.85 mixture of title compounds according to a procedure similar to that described in Preparation 3.

[0246]¹H NMR (270MHz, CDCl₃) δ7.40-7.20 (4K m), 4.80-4.57 (2.85H, m), 4.32-4.15 (1H, m), 3.85-3.80 (0.3H, m), 3.48-3.40 (0.15H, m), 3.38 (2.55H, s), 3.34 (0.45H, s), 3.05-2.92 (1.7H, m), 2.80-2.62 (2H, m), 2.58-2.40 (2 m), 2.23-2.05 (1H, in), 1.95-1.80 (1H, m)

Preparation 24

[0247] (R)-1-Benzyl-3-pyrrolidinol-tosylate

[0248] To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (1.77 g, 10 mmol) in pyridine(30 ml) was added p-toluenesulfonyl chloride (9.53 g, 50 mmol) by portions at 0° C. Afer 90 h stirring at room temperature, water was added to the reaction mixture and the mixture was extracted with ether (150 ml). The extract was washed with water, brine, dried(Na₂SO₄), and concentrated to give 3.06 g (92%) of brown oil.

[0249]¹H NMR (270MHz, CDCl₃) δ7.76 (2H, d, l=8.4Hz), 7.31 (2H d, J=8.4Hz), 7.35-7.20 (5H, m), 5.05-4.90 (1H, m), 3.61 (1H, d, J=12.8Hz), 3.54 (1H, d, J=12.8Hz), 2.76 (1H, dd, J=6:0, 11.2Hz), 2.75-2.60 (1H, m), 2.55-2.35 (2H, m), 2.44(3H, s), 2.12-2.05 (1H, m), 2.03-1 90 (1H, m).

Preparation 25

[0250] (S)-1-Benzyl-3-fluoropyrrolidine

[0251] To a solution of (R)-1-benzyl-3-pyrrolidinol-tosylate (3.06 g, 9.24mmol) in THF (30 ml) was added 10 M solution of tetrabutylammonium fluoride in THF (370 ml. 37.0 mmol) at room temperature. After 1.5 h stirring at reflux temperature, water, (37.0 mmol) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 ml×2). The combined extract was washed with water, brine, dried (Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel: 80 g, CH₂Cl₂/MeOH 50/1) to afford 1.18 g (71%) of brown oil.

[0252]¹H NMR (270MHz, CDCl₃) δ7.45-7.20 (5I, in), 5 29-5.00 (1H, m), 3 68 (1H, d, J=13.2Hz), 3.63 (E1, d, J=12.8Hz), 2.95-2.60 (3H, m), 2.55-2.38 (1H, m), 2.30-1.90 (2H, m).

Preparation 26

[0253] 2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-Fluoropyrrolidin-1-yl)-2-(R)-phenylethanol

[0254] A suspension mixture of (S)-1-benzyl-3-fluoropyrrolidine (1.18 g, 5.58 mmol) and 20% palladium hydroxide on carbon (354 mg) in EtOH (20 ml) was stirred under hydrogen atmosphere at room temperature for 21.5 h. After removal of the catalyst by Celite filtration, to this solution was added a solution of (S)-(−)-styrene oxide (791 mg, 6.58 mmol) in EtOH (5 ml). The mixture was refluxed with stirring for 3.5 h. After evaporation of the solvent, the residue was purified by column chromatography (slicagel: 80 g, CH₂Cl₂:MeOH=40:1-30.1) to give 713 mg (51.8%) of yellow oil as 0.7 to 0.3 mixture of title compounds.

[0255]¹H NMR (270MYz, CDC1₃) o 7 45-7 20 (5H, m), 5.35-5 05 (01 H, in), 5.25-4 95 (O 3 H. m), 4.71 (0.7H. dd, J=3.3, 10.6Hz), 3.95-3.75 (0.6H, m), 3.52 (0.3H, t, J=5.9Hz), 3.15-2.40 (54 H, m), 2.30-1.80 (3H, m)

Preparation 27

[0256] 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethanol and 2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-2-(S)-phenylethanol

[0257] This was prepared from 3-(S)-methoxymethoxypyrrolidine and (R)-(−)-styrene oxide in 53% yleld as 0.7 to 0.3 mixture of title compounds according to a procedure similar to that described in Preparation 2.

[0258]¹H NMR (270MHz, CDCl₃) δ7.40-7.20 (5H, m), 4.72 (0.7H, dd, J=3.3, 10.6Hz), 4.66 (0.7H, d, J=7.0Hz), 4.63 (0.7H, d, J=7.0Hz),4.634.56 (0.6H, m), 4.35-4.17 (1H, m), 3.92-3.77 (0.6H, m), 3.50 (0.3H, t, J=5.5Hz), 3 37 (2.1H,s), 3.33 (0.9H, s), 3.10-2.50 (5 4H, m), 2.25-2.00 (1H, m), 1.95-1.70 (2H, m)

Preparation 28

[0259] (R)-1-(3-Methoxymethoxyphenyl)-1.2-ethanediol

[0260] This was prepared from 3-methoxymethoxystyrene and AD-mix-β in 100% yleld according to the procedures similar to those described in Preparation 18.

[0261]¹HNM (270MHz, CDCl₃) δ7.31-7.25 (1H, m), 7.06-6.96 (3H, m), 5.18 (2H, s), 4.80 (1H, dd, J=3.7, 8.1Hz), 3.78 (1H, dd, J=3.7, 11.4Hz), 3.66 (1H, dd, J=8.1, 11.4Hz), 3.48 (3H, s).

Preparation 29

[0262] (R)-1-(3-Methoxymethoxyphenyl)-1,2-ethanediol-2-tosylate

[0263] This was prepared from (R)-1-(3-methoxymethoxyphenyl)-1,2-ethanediol in 77% yleld according to the procedures similar to those described in Preparation 19

[0264]¹H NMR (20MHz, CDCl₃) δ7.77 (2H, d, J=8.4Hz), 7.33 (2H, d, J=7.7Hz), 7.28-7.18 (1H, m), 7.00-6.92 (3H, m), 5.15 (2H, s), 5.00-4.90 (1H, m), 4.20-4.00(2H, m), 3.46 (3H, s), 2.80-2.60 (1H, m), 2.45 (3H, s)

[0265] 97% ee(by HPLC)

Preparation 30

[0266] 2-(R)-Phenyl-2-(3-pyrroline-1-yl)ethanol

[0267] This was prepared from R-(−)-2-phenylglycinol and cis-1,4-dichloro-2-butene in 58% yleld according to the procedures similar to those described in.Preparation 1.

[0268]¹H NMR (270MHz, CDCl₃) δ7.36-7.29(5H, m), 5.77(2H, s), 3 83(2H, d, J=5 9Hz), 3.66(1H,m), 3.50(4H, s).

Preparation 31

[0269] (S)-1-Benzyl-3-pyrrolidinol-tosylate

[0270] This was prepared from (S)-1-benzyl-3-pyrrolidinol and p-toluenesulfonyl chloride in 98% yleld according to the procedures similar to those described in Preparation 24.

[0271]¹H NMR (270MHz, CDCl₃) δ7.76(2H, d, J=8.4Hz), 7.33-7.26(7H, m), 4 97(1H, t, J=2.9Hz), 3.69-3.58(2H m), 2.89-2.83(I1 m), 2.73-2.68(2H, m), 2.58-2.55(1H, m), 2.44(3H, s), 2.20-2.12(1H, m), 1.99-1.93(1H, m).

Preparation 32

[0272] (R)-1-Benzyl-3-fluoropyrrolidine

[0273] This was prepared from (S)-1-benzyl-3-pyrrolidinol-tosylate in 61% yleld according to the procedures similar to those described in Preparation 25.

[0274]¹H NMR (270Mz, CDCl₃) δ7.33-7.23(5H, m), 5.28-5.04(1H, m), 3.71-3.61(2H, m), 2.91-2.67(3H, m), 2.50-2.42(1H m), 2.24-2.00(2H, m).

Preparation 33

[0275] 2-(3-(R)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(R)-Fluoropyrrolidin-1-yl)-2-(R)-phenylethanol

[0276] This was prepared (R)-1-benzyl-3-fluoropyrrolidine in 76% over all yield as 0.6 to 0.4 mixture of title compounds according to the procedures similar to those described in Preparation 26.

[0277]¹H NMR (270Mz CDCl₃) δ7.40-7.24(5H, m), 5.32-5.27(0.3H, m), 5.25-5.21 (0.2H, m), 5.11-5.07(0.3H, m), 5.07-5.01(0.2H, m), 4.71(0.6H, dd, J=3.3, 10.3Hz). 3.90-3.78(0.6H, m), 3.55-3.51(0.4H, m), 3.13-2.44(5.4H, m), 2.23-1.94(2H, m).

Preparation 34

[0278] 2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(R)-phenylethanol and 2-(3-(S)-Fluoropyrrolidin-1-yl)-2-(S)-phenylethanol

[0279] This was prepared from 3-(S)-fluoropyrrolidine and (R)-(+)-styreneoxide in 72% yleld as 0.7 to 0.3 mixture of the title compounds according to the procedures similar to those described in Preparation 26.

[0280]¹H NMR (270MHz, CDCl₃) δ7.39-7.24(5H, m), 5.31-5.28(0.35H, m), 5.23-5.22(0.15H, m), 5.12-5.07(0.35H, m), 5.06-5.01(0.15W, m), 4.73-4.68(0.7H, m), 3.88-3.79(0.7H, m), 3.54-3.50(0.3W, m), 3.13-2.44(5.3H, m), 2.20-1.93(2H, m).

Preparation 35

[0281] (S)-1-Benzyl-3-chloropyrrolidine

[0282] To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (886 mg, 50 mmol) in CCl₄(20 ml) was added triphenylphosphine(1.574 g, 6.0 mmol) at rt. After 20 h stirring at reflux temperature, the solvent was evapolated. Saturated NaHCO₃ aqueous solution and water was added to the residue, and the mixture was extracted with AcOEt. The extract was brine, dried(Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel; lOOg, CH₂Cl₂/MeOH: 50/1-45/1) to give 706 mg(72%) of pale yellow oil.

[0283]¹H NMR (270MHz, CDCl₃) δ7.33-7.23(5H, m), 4.42-4.33(1H, m), 3.73-3.61(2H, m), 3.09(1H, dd, J=6.6, 10.6Hz), 2.81-2.61(3FL m), 2.48-2.35(1H, m), 2.13-2.03(1H, m)

Preparation 36

[0284] 2-(3-(S)-Chloropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-Chloropyrrolidin-1-yl)-2-(R)-phenylethanol

[0285] To a stirred solution of (S)-1-benzyl-3-chloropyrrolidine(695 mg, 3.55 mmol) in dichloroethane(10 ml) was added 1-chloroethyl chloroformate(0.38 ml, 3.53 mmol) at 0° C. The mixture was stirred at 0° C. for 10 min and refluxed for 1.5 h. After cooling down to rt, the solvent was evapolated. The residue was dissolved in MeOH(5 ml) and refluxed for 1 h. After cooling down to rt, the solvent was evapolated to give 787 mg of brown solid.

[0286] Title compounds were prepared from the above solid and (S)-(−)-styreneoxide in 39% over all yleld as 0.67 to 0.33 mixture of the title compounds according to the procedures similar to those described in Preparation 2.

[0287]¹H NMR (270MHz, CDCl₃) δ7.39-7.27(5H, m), 4.70(0.67H, dd, J=3 3, 10.3Hz), 4.454 4.40(0.67H, m), 4.38-4.32(0.33H, m), 3.91-3.02(2.33H, m), 2.88-2.56(4H, m), 2.50-2.31(1H, m), 2.17-2.03(1H, m).

Preparation 37

[0288] Methlyl 3-fluoro4-nitrobenzoate

[0289] A mixture of 3-fluoro-4-nitrobenzoic acid(2.07 g, 11.2 mmol) and cH₂SO₄(0.5 ml) in MeOH(10 ml) was refluxed for 8 h. The solvent was evapolated The residue was dissolved in AcOEt and washed with saturated NaHCO₃ aqueous solution, water, brine, dried (NazSO,), and concentrrated to give 2.14 g(96%) of ivory solid.

[0290]¹H NMR (270MHz, CDCl₃) δ8.15-8.07(1H, m), 7.99-7.96(l1i, m), 7.95-7.92(1H m), 3.99(3H, S).

Preparation 38

[0291] Methyl 4-amino-3-fluorobenzoate

[0292] A mixture of methilyl 3-fluoroAnitrobeazoate(2.14 g, 10.8 mmol) and iron powder(2.63 g) in acetic acid(22 ml) was stirred at 50° C. for 2.5 h. After cooling down to room temperature, CH₂Cl₂(100 ml) and water(300 ml) was added to the mixture and filtered to remove iron powder. The organic layer was separated and the aqueous layer was extracted with CH₂Cl₂(70 ml×2). The CH₂Cl₂ solution was combined, washed with water, brine, dried(Na₂SO₄), and concentrated to give 1.77 g(97%) of pale brown solid

[0293]¹H NMR (270MHz, CDCl₃) δ7.70-7.62(2H, m), 6.79-6.70(1H, m), 4.13(2H, br, s), 3.86(3H, S).

Prenaration 39

[0294] Methlyl 3-fluoro-4-methylaminobenzoate

[0295] To a solution of methlyl 4-amino-3-fluorobenzoate(1.77 g, 10.5 mmol) in CH₂Cl₂(50 ml) was added Na₂CO₃(3.33 g, 31.4 mmol) and trifluoroacetic anhydride(2.96 ml, 20.9 mmol) at room temperature. After stirring for 2.5 h, the solid was filtered off. The filtrate was washed with water, brine, dried(Na₂SO₄), and concentrated to give 2.70 g(97%) of white solid. To a solution of this solid(2.70 g, 10.2 mmol) in DMF(48 ml) was added Na₂CO₃(16.9 g, 160 mmol) and iodomethane(20.8 ml, 334 mmol) at 0° C. After stirrng for 2 h at 0° C., for 1 h at room temperature, the mixture was poured into 2NHCI with ice and extracted with AcOEt toluene =2:1(200 ml×2). The extract was washed with water, brine, dried(Na₂SO₄), and concentrated to give 3.06 g(quant) of brown oil. This oil was dissolved in MeOH(25 ml) and 7% K₂CO₃ solution(12.5 ml) was added at 0° C. After stirring for 2 h at 0° C., for 4 h at room temperature, 7% K₂CO₃ solution(12.5 ml) was added. After stirring for 1.5 h at room temperature, the mixture was acidified with 5NHCl and MeOH was evapolated. The residue was extracted with AcOEt. The extract was washed with water, brine, drie4d(Na₂SO₄), and concentrated to give 1.83 g(98%) of pale brown solid.

[0296]¹H NMR (270MHz, CDCb) δ7.8-7.72(1H, m), 7.62(1H. dd, J=1.8, 12.5Hz), 6.63 (1H, t, J=8.6Hz), 4.40(1H, br. s), 3.86(3H, S), 2.94(3H, d, J=5.1lHz).

Preparation 40

[0297] 5-[N-tert-Butoxycarbonyl)-N-methylamino]-N′-2propylpicolinamide

[0298] To a solution of 5-(N-(tert-butoxycarbonyl)-N-methylamino]picolinic acid(1.93 g, 7.66 mmol) and triethylamine(1.60 ml, 11.5 mmol) in DMF(0.678 ml) and CH₂Cl₂(14 ml) was added oxalyl chloride(0.989 ml, 11.3 mmol) dropwise at room temperature. After stimng for 30 min at room temperature, the solvent was evapolated The residue was dissolved in CH₂Cl₂( 14 ml). This solution was added dropwise to a stirried, cooled solution of n-propylamine(0.756 ml, 9.19 mmol) and triethylamine(3.20 ml, 23.0 mmol) in CH₂Cl₂(28 ml) while the temperature was kept below 15° C. After stirring for 15 h at room temperature, the mixture was washed with water, brine, dried(Na₂SO₄), and concentrated to mve brown oil, which was purified by column chromatography (silica gel; 100 g, CH₂Cl₂/MeOH: 60/1) to give 1.82 g (81%) of pale brown oil.

[0299]¹H N (270MHz, CDCl₃) δ8.49(1H, d, J=2.6Hz), 8.16(1H, d, J=8.4Hz), 7 95(1H, br s), 7.71(1H, dd, J=2.6, 8.4Hz), 3.50-3.40(2H, m), 3.32(3H, S), 1.75-1.55(2H, m), 1.48(9H, s), 1.00(3H, t, J=7.3Hz).

Preparation 41

[0300] 5-N-Methylamino-N′-propylpicolinamide

[0301] A solution of 5-[N-(tert-butoxycarbonyl)-N-fmethylamino]-N′-propylpicolinamide(1.82 g, 6.21 mmol) in trifluoroacetic acid(30 ml) was stirred at 0° C. for 2 h. After removal of the solvent, the residue was dissolved in CH₂Cl₂ and 25% ammonia solution. The organic layer was separated and washed with brine, dried(Na₂SO₄), and concentrated to give 1.20 g(100%) of brown solid.

[0302]¹H NMR (270MHz, CDCl₃) δ8.01(1H, d, J=8.4Hz), 7.88(1H, d, J=2.9Hz), 7.78(1 H, br s), 6.90(1H, dd, J=2.9, 8.4Hz), 4.17(1H, br. s), 3.45-3.35(2H, m), 2.91(3H, d, J=5.lHz), 1.75-1.55(2H, m), 0.98(3H, t, J=7.3Hz).

Preparation 42

[0303] 4-N-Hydroxyamino-N′-propylbenzamide

[0304] To a solution of 4-nitro-N-propylbenzamide(2.75 g,13.2 mmol) and ammonium chloride(812 mg, 15.2 mmol) in EtOH(20 ml) and water(10 ml) was added zinc powder(1.70 g, 26.0 mmol) portionwise with water cooling. After stirring for 30 min at room temperature, zinc powder(0.50 g, 7.65 mmol) was added to the mixture and stirred for 30 min at room temperature. The solid was removed through celite and washed with MeOH. The filtrate and washings were combined and concentrated to give yellow solid, which was purified by column chromatography (silica gel, 130 g, CH₂Cl₂/MeOH. 25/1-10/1) to give 2.06 g(80%) of ivory solid.

[0305]¹H NMR (270MHz, CDCl₃-DMSO-d6) δ8.32(1H, d, J=2.2Hz), 7.72(2H, d, J=8.4Hz). 7.25-7.10(1H, m), 6.95(2H, d, J=8.8Hz), 3.45-3.30(2H m), 2.91(1H, s), 1.70-1 5;(2H, m), 0.96(3H, t, J=7.3Hz).

Presaration 43

[0306] 4-Amino-2-chloro-N′-propylbenzamide

[0307] A mixture of 4-amino-2-chlorobenzoic acid(3.00 g, 17.5 mmol), n-propylamine(2.88 ml, 35.0 mmol) and WSC(6.71 g, 35.0 mmol) in CH₂Cl₂(35 ml) was stirred at room temperature for 16 h. The mixture was washed with water, brine, dried(Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 180 g, CH₂Cl₂/MeOH: 30/1-10/1) to give 2.32 g(62%) of pale ivory solid.

[0308]¹H NMR (270MHz, CDCl₃) δ7.64(1H, d, J=8.4Hz), 6.64(1H, d, J=2.6Hz), 6.57(1H, dd, J=2.6, 8.4Hz), 6.44(1H, br. s), 3.97(2H, br. s), 3.50-3.30(2H, mn), 1.75-1.55(2H, m), 0.99(3H, t, J=7.3Hz).

Preparation 44

[0309] 2-Chloro-4-methylamino-N′-propylbenzamide

[0310] A mixture of 4-amino-2-chloro-N′-propylbenzamide(2.32 g, 10.9 mmol), iodomethane(0.68 ml, 10.9 mmol) and K₂CO₃(1.51 g, 10.9 mmol) in DMF(50 ml) was stirred at room temperature for 20 h. Water was added to the mixture and extracted with AcOEt: toluene=1:1. The etraa was washed with water, brine, dried(Na₂SO₄), and concentrated to give pale brown solid, which was purified by column chromatography (silica gel, 120 g, CH₂Cl₂/MeOH 40/1) to give 887 mg(36%) of pale brown solid.

[0311]¹H NMR (270w CDCl₃) δ7.57(1H, d, J=8.4Hz), 6.80(1H, br. s), 6.53(1H, d, J=2.2Hz), 6.50(1H, dd, J=2.2, 8.4Hz), 5.004.80(1H, m), 3.45-3 30(2H, m), 2.82(3H, d, J=5.lHz), 1.75-1.55(2K m), 0.99(3H, t, J=7.3Hz).

Preparation 45

[0312] 4-Methylamino-N′-(2-(S)-hydroxypropyl)benzamide

[0313] This was prepared from 4-(methylamino)benzoic acid and (S)-(+)-1-amino-2-propanol in 22% yleld according to the procedures similar to those described in Preparation 43.

[0314]¹H NMR (270MHz, CDCl₃-DMSO-d6) δ7.69(2H, d, I=8.4Hz), 7.14(1H, br. s), 6.56(2H, d, J=8.8Hz), 4.60-4.30(2H, m), 3.98-3.94(1H, m), 3.64-3.55(1H, m), 3.28-3.18(1H, m), 2.85(3H, s), 1.20(3H, d, J=6.2Hz).

Preparation 46

[0315] 4-Methylamino-N′-(2-(R)-hydroxypropyl)benzamide

[0316] This was prepared from 4-(methylamino)benzoic acid and (R)-(−)-1-amino-2-propanol in 41% yleld according to the procedures similar to those described in Preparation 43.

[0317]¹H NMR (270z, CDCl₃-DMSO-d6) δ7.68(2H, dd, J=1.8, 7.0 Hz), 7.12(1H br, s), 6.55(2H, dd, J=1.8, 7.0Hz), 4.50(1H, br. s), 4.37(1H, br. s), 3.98-3.93(1K m), 3.64-3.55(1H, m), 3.28-3.18(1H m), 2.85(3H, d, J=4 SHz), 1.20(3H, d, J=6.2Hz)

Preparation 47

[0318] 4-Methylamino-N′-propylbenzamide

[0319] This was prepared from 4-(methylamino)benzoic acid and n-propylamine in 82% yleld according to the procedures similar to those described in Preparation 43.

[0320]¹H NMR (270MHz, CDCl₃) δ7.63(2H, d, J=8,8Hz), 6.56(2H, d, J=8.8Hz), 6.05(1H, br s), 4.11(1H, br. s), 3.45-3.30(2H, m), 2.86(3H, s), 1.70-1.50(2K m), 0.97(3H, t, J=7.3Hz).

Preraration 48

[0321] 4-(N-(Benzyloxycarbonyl)-N-methylamino]-N′-(2,2,3,3,3-pentafluoropropyyl)benzamide

[0322] To a solution of 4N-(benzyloxycarbonyl)-N-methylaminolbenzoic acid (100 mg, 0.351 mmol) in CH₂Cl₂(1 ml) was added oxalyl chloride(0.122 ml, 1.40 mmol) and DMF(0.026 ml) at room temperature. After stirring for 4 h at room temperature, the solvent was evapolated. The residue was dissolved in CH₂Cl₂(10 ml). To this solution was added 2,2,3,3,3-pentafiuoropropylamine(523 mg, 351 mmol) and tnethylamine(0.372 ml, 2.67 mmol) at room temperature. After stirring for 18 h at room temperature, saturated NAHCO₃ aqueous solution was added to the mixture and extracted with CH₂Cl₂. The extract was washed with brine, dried(Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 30 g, CH₂Cl₂ only-CH₂Cl₂/MeOH: 50/1) to give 532 mg(72%) of title compound.

[0323]¹H NMR (270MHz, CDCl₃) δ7.75(2H, d, J=8.8Hz), 7.39-7.31(7H, m), 6.42-6.31(1H, m), 5.19(2H, s), 4.17(2H, ddd, J=6.2, 14.7, 14.7Hz), 3.36(3H, s).

Preparation 49

[0324] 4-[N-(Benzyloxycarbonyl)-N-methylaminol-N′-tert-amylbenzamide

[0325] This was prepared from 4-(N-(benzyloxycarbonyl)-N-methylamino]benzoic acid and tert-amylarine in 22% yield according to the procedures similar to those described in Preparation 48.

[0326]¹H NMR (270MHz, CDCl₃) δ7.69(2H, d, J=8.4Hz), 7.32-7.29 (7H, m), 5.86-5.75 (1H, m), 5.17(2H, s), 3.33(3H, s), 1.88-1.80(2H, m), 1.40(6H, s), 0.89(3H, t, J=7.3Hz).

Preparation 50

[0327] 4-[N-(Benzyloxycarbonyl)-N-methylaminol-N′-tert-butylbenzamide

[0328] This was prepared from 4-(N(benzyloxycarbonyl)-N-methylamino]benzoic acid and tert-butylamine in 93% yleld according to the procedures similar to those described in Preparation 48.

[0329]¹H NMR (270MHz, CDCl₃) δ7.69 (2H, d, J=8.8Hz), 7.32-7.29 (7H, m), 5.89 (1H, br s), 5.17(2K, s), 3.33(3H, s), 1.46(9H, s).

Preparation 51

[0330] 4-Methylamino-N′-(2,2,3,3,3,-pentafluoropropyl)benzamide

[0331] A suspension mixture of 4-[N-(benzyloxycarbonyl)-N-methylamino]-N′-(2,2,3,3,3,-pentafluoropropyl)benzamide(532 mg, 1.28 mmol) and 10% palladium carbon(41 mg) in MeOH(5 ml) was stirred under hydrogen atmosphere at room temperature for 6 h. The catalyst was removed through Celite and washed with MeOH. The filtrate and washings were combined and concentrated to give 345 mg(96%) of title compound.

[0332]¹H NMR (270MHz, CDCl₃) δ7.66 (2H, d, J=8 4Hz), 6.58 (2H, d, J=8.4Hz). 6.15-6.12(1H, m), 4.23-4.09(3H, m), 2.89(3H, d, J=4.4Hz).

Preparation 52

[0333] 4-Methylamino-N′-tert-amylbenzamide

[0334] This was prepared from 4-[N-(benzyloxycarbonyl)-N-methylarmno]-N′-tert-amylbenzamide in 88% yleld according to the procedures similar to those described in

Preparation 51

[0335]¹H NMR (270MHz, CDCl₃) δ 7.58(2H, d, J=8.4Hz), 6.56(2H, d, J=8.8Hz), 5.70(1H, br s), 4.00(1H, br. s), 2.87(3H, s), 1.83(2H, q, J=7.7Hz), 1.39(6H, s), 0.89(3H, c, J=7.7Hz).

Preparation 53

[0336] 4-Methylamino-N′-tert-butylbenzamide

[0337] This was prepared from 4-[N-(benzyloxycarbonyl)-N-methylamino]-N′-tert-butylbenzamide in 100% yield according to the procedures similar to those described in

Preparation 51.

[0338]¹H NMR (270MHZ, CDCl₃) δ7.58(2H, d, J=8.4Hz), 6.56(2H, d, J=8.8Hz), 5.78(1H, br s), 2.86(3H, s), 1.45(9H, s).

EXAMPLE 1

[0339] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino}-N′-propylbenzamide

[0340] (i) Methyl 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate

[0341] To a stirred solution of the mixture of 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol (2.01 g, 8.00 mmol) and triethylamune (1.34 ml, 9.60 mmol) in CH₂C₁₂ (35 ml) was added methanesulfonyl chloride (0.744 ml, 9.60tnnol) dropwise at 0° C. (ice bath). After 5.5 h stirring at room temperature, the reaction mixture was washed with saturated NaHCO₃ aqueous solution, brine, dried (Na₂SO₄), and concentrated to give 2.16 g of brown viscous oil. To this oil was added Methyl 4-methylaminobenzoate (1.45 g, 8.80 mmol) and ethanol (16 ml) and the mixture was stirred at reflux temperature for 1.5 h. The solvent was evaporated. The residue was dissolved in CH₂Cl₂ and washed with saturated NaHCO₃ aqueous solution and brine, dnred (Na₂SO₄), and concentrated to give brown oil, which was purified by column chromato-graphy (silica gel 150 g, CH₂Cl₂/MeOH: 100/1-35/1) to afford 1.99 g(62.5%) of brown oil.

[0342]¹H NMR (270MHz, CDCl₃) δ7.89 (2H, d, J=9.2Hz), 7.35-7.20 (5H, m), 6.78 (2H, d, J=9.2Hz), 5.17 (1H, dd, J=6.6, 8. 1Hz), 4.59 (1H, d, J =7.0Hz), 4.55 (1H, d, J=7.0Hz), 4.224.12 (1H, m), 3.85 (3H, s), 3.30 (3H, s), 3.10 (1H, dd, J=6.2, 12.8Hz), 3.03 (1H, dd, J=8.4, 12.8Hz), 2.86 (3H, s), 2.85-2.80 (1H, m), 2.77-2.67 (1H, m), 2.65-2.53(2H, m), 2.05 (1H ddd, J=7.5, 13.9, 13.9Hz), 1.83-1.70(1H, m).

[0343] (ii) 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid

[0344] A mixture of methyl 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)benzoate (1.99 g, 5.00 mmol) and 4N-NaOH (12.5 ml, 50.0 mmol) in MeOH (35 ml) was stirred at 75° C. for 3 h. The mixture was neutrallized with 5N-HCl at 0° C. The solvent was removed in vacuo. CH₂Cl₂ was added to the residue and insoluble solid was removed by filtration. The filtrate was concentrated to give 2.04 g (quant) of pale brown amorphous.

[0345]¹H NMR (270MHz, CDCl₃) δ7.93 (2H, d, J=8.8Hz), 7.40-7.10 (5H, m), 6.81 (2H, d, J=9.2Hz), 5.85 (1H, br. s), 5.26 (1H, dd, J=6.2, 8.1Hz), 4.60 (1H, d, J=7.0Hz), 4.56 (1H, d, J=7.0Hz), 4.254.15 (1H, m), 3.30 (3H, s), 3.20-3.05 (2H, m), 2.97 (1H, dd, J=6.2, 9.9Hz), 2.87 (3H, s), 2.80-2.65 (3H, m), 2.15-2.00 (1H, m), 1.90-1.75 (1H, m)

[0346] (iii) 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)phenylethyl]-N-methylamino}-N′-propylbenzamide

[0347] To a stirred solution of 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid (2.04 g, 5.00 mmol) and n-propylamine (0. 822 ml, 10.0 mmol) in CH₂Cl₂ (35 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride (1.92 g, 10 mmol) at room temperature.

[0348] After 15 5 hr stirring, the reaction mixture was washed with water and bnne. dried(Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 100 g, CH₂Cl₂/MeOH: 25/1) to give 1.52 g(72%) of pale brown amorphous.

[0349]¹H NMR (270MHz, CDCl₃) δ7.65 (2K d, J=8.8Hz), 7.35-7.20 (5H, m), 6.79 (2H, d, J=9.2Hz), 6.05-5.90 (1H, m), 5.14 (1H, dd, J=6.6, 8.1Hz), 4.59-(1H, d, J=7.0Hz) 4.55 (1H, d, J=7.0Hz), 4.24-4.10 (1H,m), 3.39 (2H, dd, J=6.6, 13.9Hz), 3 30 (3H, s). 3.14-2.96 (2H, m), 2.90-2.80 (1H, m), 2.85 (31i, s), 2.78-2.52 (3H, m), 2.14-1.96 (1H, m), 1.84-1.70 (1H, m), 1.68-1 56 (21H, m), 0.97 (3H, t, J=7.3Hz)

EXAMPLE 2

[0350] Preparation of 4-(N-(2-(3(S)-Hydroxypyrrolidin-1-yl)-1-S)-phenylethyl]-N-methylaminol-N′-propylbenzamide

[0351] A mixture of 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaminQ}-N′-propylbenzamide (1.52 g, 3.58 mmol) and 10% HCl in MeOH (25 ml) was stirred at room temperature for 6 h. The solvent was evaporated The residue was basified with 25% ammonium hydroxide, extracted with CH₂Cl₂. The extract was washed with brine, dried (Na₂SO₄) and concentrated to give pale brown amorphous, which was purified by column chromatography (silica gel, 65 g, CH₂Cl₂/MeOH: 20/1-15/1) to give 1.21 g (89%) of pale brown amorphous

[0352]¹H NMR (270MHz, free amine, CDCl₃) δ7.66 (2H, d, J=9.2Hz), 7.40-7.20 (5H, m), 6.81 (2H, d, J=9.2Hz), 6.05-5.90 (1H, m), 5.15 (1, dd, J=5.9, 12.8Hz), 42-4 16 (1H, m), 3.46-3.32 (2H, m), 3.13 (1H, dd, J=92, 12.8Hz), 3.03 (1H dd, J=5.9. 12.8Hz), 2.90 (1H, ddd, J=5.0, 8.5, 8.5Hz), 2.84 (3H, s), 2.73 (1H, d, J=9.9Hz), 2.56 (1H, dd. J=4.6, 9.7Hz), 2.32 (1H, ddd, J=6.1, 9.0, 9.0Hz), 2.18-2.00 (1H, m), 1.90-1.50 (4H, m). 0.98 (3H, t, J=7.3Hz).

[0353] 600 mg of this amorphous was dissolved in 10% HCl in MeOH (10 ml) The solvent was concentrated to give 625 mg of HCl salt as pale brown amorphous.

[0354] IR(KBr):3300, 1610cm⁻¹. MS m/z: 382(M+H) Anal. Calcd for C₂₃H₃₁N₃O₂·HCl·1.5H₂O C, 62.08; K 7.93; N, 9.44. Found C, 62.29; H 8.01; N, 9.42.

EXAMPLE 3

[0355] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-methylbenzamide

[0356] This was prepared from 4-{N-[2-(3-(S)methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylarnino}benzoic acid and methylarnine hydrochlonde in 26% yleld according to a procedure similar to that described in Example 1 (iii).

[0357]¹H NMR (270MHz, CDCl₃) δ7.64 (2K d, J=8.8Hz), 7.40-7.20 (5H, m), 6.79(2H, d, J=8.8Hz), 6.02 (1H, br. s), 5.13 (1H, dd, J=6.6, 8.1Hz), 4.59 (1H, d, J=7.0Hz), 4.55 (1H, d, J=6.6Hz), 4.204.13 (1H, m), 3.30 (3H, s), 3.15-3.00 (2H, m), 2.97 (3H, d, J=5.1Hz), 2.90-2.80 (1H, m), 2.83 (3H, s), 2.75-2.55 (3H, m), 2.05 (1H, ddd, J=7.7, 14.3, 13.9Hz), 1.90-1.70 (1H, m).

EXAMPLE 4

[0358] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-methylbenzamide

[0359] This was prepared from 4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaminol-N′-methylbenzamide in 82% yleld according to a procedure similar to that described in Example 2.

[0360]¹H NMR (270MHz, free amine, CDCl₃) δ7.66 (2, d, iJ=9.2Hz), 7.40-7.20 (5H, m), 6.81 (2H, d, J=8.8Hz), 6.00-5.95 (1H, m), 5.15 (1H dd, J=6.0, 9.0Hz), 4.25-4.20 (1H, m), 3.13 (1H, dd, J=9.2, 12.8Hz), 3.03 (1H, dd, J=5.9, 12.8Hz), 2.98 (3H, d, J=5.1Hz), 2.95-2.80 (1H, m), 2.83 (3H, s), 2.74 (1H, d, J=9.9Hz), 2.55 (1H, dd, J=4.6, 9 7Hz), 2.35-2.25 (1H, m), 2.17-2.05 (1H, m), 1.80-1.60 (2H, m) HCl salt:amorphous solid. IR(KBr): 3350, 1610cm⁻¹. Anal. Calcd for C₂₁H₂₇N₃O₂·HCl·1.2H₂O:C, 61.29, H, 7.45; N, 10.21 Found: C,61.68 ; H, 7.84; N,10.20.

EXAMPLE 5

[0361] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-( S)-phenylethyll-N-methylamino}-N′-ethylbenzamide

[0362] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaminolbenzoic acid and ethylarnine hydrochloride in 33% yield according to a procedure similar to that described in Example 1 (iii).

[0363]¹H NMR (270MHz, CDCl₃) δ7.64 (2H d, J=8 8Hz), 7.34-7.24 (5H, m), 6 79 (2H, d, J=8.8Hz), 5.95-5.83 (1H, m), 5.13 (1H, dd, J=7 0, 7.5Hz), 4.59 (1H, d, J=7.0Hz), 4.55 (1H, d, J=6.6Hz), 4.25-4.14 (1H, m), 3.52-3.42 (2H, m), 3.30 (3H, s), 3.10-3.01 (2H, m), 2.89-2.80 (1H, m), 2.83 (3H, s), 2.75-2.53 (3H, m), 2.11-2.01 (1H, m), 1.80-1.74 (1H, m), 1.23 (3H, t, J=7.1Hz)

EXAMPLE 6

[0364] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaminol-N-ethylbenzamide

[0365] This was prepared from 4-{N-(2-(3-(S)-methoxymethoxypyrrolidia-1-yl)-1-(S)-phenylethyl]-N-methylamino)-N′-ethylbenzamide in 43% yield according to a procedure simnilar to that described in Example 2.

[0366]¹H NMR (270MHz free amine, CDCl₃) 6 7.65 (2K, d, J=8.8Hz), 7 34-7.23 (5H, m), 6.80 (2H, d, J=8.8Hz), 6.01 (1H, br.s), 5.14 (1H, dd, J=6.2, 8.8Hz), 4.22-4,18 (1H, m), 3.50-3.40 (2HI m), 3.11 (1H, dd, J=8.8, 12 SHz), 3.02 (1I, dd, J=5.9, 12.8Hz), 2.92-2.85 (1H, m), 2.82 (3H, s), 2.70 (IKI, d, J=9.5Hz), 2.57 (1H, dd, J=4.8, 9 9Hz), 2.37-2.29 (1H, m), 2.12-2.01 (2H, m), i 6S-1 60 (1H,m), 1.21 (3H, t, J=7 3Hz)

[0367] HCI salt:amorphous solid. IR(KBr): 3350, 1610cm⁻¹. Anal. Calcd for C₂₂H₂₉N₃O₂·HCl·4H₂O C, 55 72, H, 7.70, N, 8.97 Found: C, 55.51 ,H. 8.05 N, 8.83.

EXAMPLE 7

[0368] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-butylbenzamide

[0369] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and n-butylamine in 40% yield according to a procedure similar to that described in Example 1 (iii).

[0370]¹H NMR (270MHz, CDCl₃) δ7.63 (2H, d, l=9.2Hz), 7.34-7 24 (5H, m), 6.79 (2H, d, J=9.2Hz), 6.00-5.85 (1H, m), 5.12 (1H, dd, J=6.6, 7.1Hz), 4.59 (1H, d, J=6.6Hz), 4.55 (1H, d, J=6.6Hz), 4.194.15 (1H, m), 3.50-3.40 (2H, m), 3.29 (3H, s), 3.07-3.02 (2H, m), 2.90-2.80 (1H, m), 2.84 (3H, s), 2.72-2.57 (3H, m), 2.08-2.01 (1H, m), 1.78-1.60 (1H, m), 1.58-1.36 (4H, m), 0.94 (3H, t, J=7.3Hz)

EXAMPLE 8

[0371] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-butylbenzamide

[0372] This was prepared from 4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-butylbenzamide in 59% yield according to a procedure similar to that descnbed in Example 2.

[0373]¹H NMR (270MHz, free amnine, CDCl₃) δ7.65 (2H, d, J=8.8Hz), 7.35-7.24 (5H, m), 6.80 (2H, d, J=8.8Hz), 5.82-5.78 (1H, m), 5.15 (1H, dd, J=5.9, 8.8Hz), 426-4.24 (1H,m), 3.43 (2H, dd, J=7.0, 12.8Hz), 3.13 (1H, dd, J=8.8, 12.8Hz), 3.03 (1H, dd, J=6.2, 12.8Hz), 2.93-2.85 (1H, m), 2.84 (3H, s), 2.73 (1H, d, J=9.5Hz ), 2.56 (1H, dd, J=4.8, 9.5Hz), 2.37-2.28 (1H, m), 2.10-2.06 (1H, m), 1.72-1.52 (4H, m), 1.47-1 25 (2H, m), 0.95 (3H, t, J=7.3Hz) HCl salt:amorphous solid. IR(KBr): 3350, 1610cm⁻¹. MS mnz: 396(M+H)⁺. Anal. Calcd for C₂₄H₃₃N₃O₂-HCl·1.4H₂O:C, 63.05; 8.11; N, 9.19 Found: C, 63.06; H, 8.04; N, 8.98.

EXAMPLE 9

[0374] Preparation of 4-{N-[1-(S)-Phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-pentylbenzamide

[0375] This was prepared from 2-(R)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol in 33% over all yield according to a procedure similar to that described in Example 1 (i)-(iii).

[0376]¹H NMR (270MHz CDCl₃) δ7.70-7.60 (2H, m), 7.40-7.20 (5H, m), 6.79 (2H, d, J=8.8Hz), 6.00-5.90 (1H, m), 5.20-5.10 (1H, m), 4.60-4.55 (0.6H, m), 4.50-4 40 (0.4H, m), 4.35-4.20 (1H, m), 3.90-3.72 (1H, m), 3.50-3.35 (3H, m), 3 15-2 90 (3H, m), 2.84 (1.8H, s), 2.83 (1.2H, s), 2.80-2.50 (3H, m), 2.20-1.95 (1H, m), 1.90-1.25 (13H, m), 0.91 (3H, t, J=7.0Hz).

EXAMPLE 10

[0377] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-pentylbenzamide

[0378] This was prepared from 4-{N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethyl]-N-methylamino}-N′-pentylbenzamide in 98% yield according to a procedure similar to that described in Example 2.

[0379]¹H NMR (270MHz, free amine, CDCl₃) δ7.65 (2H, d, J=9.2Hz), 7.40-7.20 (5H, m), 6.81 (2H, d, J=8.8Hz), 6.00-5.90 (lHK m), 5.16 (1H, dd, J=6.0, 9.0Hz), 4.26-4.13 (1H,m), 3.50-3.37 (2H, m), 3.13 (1H, dd, l=9.2, 12.8Hz), 3.03 (1H dd. 6.3, 12.8Hz). 2.93-2.80 (1H, m), 2.84 (3H, s), 2.73 (1H, d, J=9 2Hz), 2.56 (1H, dd, J=4.8, 9.5Hz). 2.37-2.28 (1H, m), 2.17-2.00 (1H, m), 1.90-1 55 (4H, m), 1.50-1.30(4H, m), 0.93 (3H, t, J=7.3Hz) HCl salt:amorphous solid. IR(KBr) 3350, 1610cm⁻¹. Anal. Calcd for C₂₅H₃₅N₃O₂·HCl·0.25H₂O C, 66.65; H 8.17, N, 9.33 Found. C, 66.57; H, 8.47; N,9.31.

EXAMPLE 11

[0380] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-isopropylbenzamide

[0381] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyt]-N-methylamino)benzoic acid and isopropylamine in 15% yield according to a procedure similar to that described in Example 1 (iii).

[0382]¹H NMR (270MHz, CDCl₃) δ7.63 (2H, d, J=9.2Hz), 7.34-7.21 (SH, m), 6.78 (2H, d, J=9.6Hz), 5.75-5.72 (I1, m), 5.12 (1H, dd, J=6.2, 8.8Hz), 4.59 (1H, d, J=6.6Hz), 4.55 (1H, d, J=6.6Hz), 4.304.23 (1H, m), 4.184.14 (IF, m), 3.30 (3H, s), 3.06-3.03 (2H, m), 2.90-2.80 (1H,m), 2.85 (3H, s), 2.81-2.72 (I, m), 2.66-2.57 (2R m), 2.08-2.01 (1H, m), 1.79-1.76 (1I, m), 1.23 (6H, d, J=6.6Hz)

EXAMPLE 12

[0383] Preparation of 4-{-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-isopropylbenzamide

[0384] This was prepared from 4-{N-12-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)-N′-isopropylbenzamide in 80% yield according to a procedure similar to that described in Example 2.

[0385]¹H NM (270MHz, free amme,CDCl₃) δ7.64 (2H, d, J=8.8Hz), 7.34-7.22 (5R H), 6.80 (2H, d, J=8.8Hz), 5.79-5.77 (IEI, m), 5.15 (IK, dd, J=6.2, 8.8Hz), 4.304 19 (2H, m), 3.13 (1H, dd, J=9.2, 12.3Hz), 3.03 (1H, dd, J=6.2, 12.8Hz), 2.93-2.84 (iH, m), 2.82 (3H, s), 2.72 (I1, d, J=9.5Hz), 2.57 (1H, dd, J=4.8, 9.9Hz), 2.38-2.29 (1H, m), 2.14-2.02 (2H, m), 1.68-1.58 (I1, m), 1.23 (6H, d, J=6.6Hz) HCl salt:amorphous solid. 1R(KBr) 3350, 1610 cm⁻¹. MS m/z: 382(M+H)⁺. Anal. Calcd for C₂₃H₃₁N₃O₂·HCl·1.9H₂O:C, 61.09; H, 7.98; N, 9.29 Found: C, 61.16; H, 7.61 , N, 9.12.

EXAMPLE 13

[0386] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-phenylbenzamide

[0387] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and aniline in 48% yield according to a procedure similar to that described in Example1(iii)

[0388]¹H NMR (270MHz, CDCl₃) δ7.63 (2H, d, J=8 8Hz), 7.69 (1H, br s), 7 62 (2H, d, J=7.7Hz), 7.40-7.24 (7H, m), 7.11 (1H, t, J=7 3Hz), 6.88-6.80 (2H, m), 5.18 (1H, dd, J=7.7, 15.0 Hz), 4 60 (1H, d, J=7 OHz), 4 56 (I1 d, J=7.0 Hz), 4.25-4.10 (1H, m), 3.31 (3H, s), 3.15-3.05 (2H, m), 2.89 (3H, s), 2.95-2.80 (1H, m), 2.80-2.55 (3H, m), 2.15-2.00 (1H, m), 1.90-1.70 (1H, m)

EXAMPLE 14

[0389] Preparation of 4-{-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)-N′-phenylbenzamide

[0390] This was prepared from 4-{N-[2-(3-(S)methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-phenylbenzamide in 16% yield according to a procedure sirnilar to that described in Example 2.

[0391]¹H NMR (270MHz, free amine, CDCl₃) δ7.84 (1H, br s), 7.76 (2H, d, J=8.8Hz), 7.66-7.60 (2H, m), 7.40-7.24 (7H, m), 7 10 (I H, t, J=7 3Hz), 6.84 (2H, d, J=9.2Hz), 5.18 (1H, dd, J=6.2, 8.8Hz), 4.304.17 (1l, m), 3.15 (11, dd, J=9.2, 12.8Hz), 3.05 (1H, dd, J=5.9, 12.8Hz), 3.00-2.85 (1H, m), 2 85 (3H, s), 2.74 (1H, d, J=9 5Hz), 2.59 (1H, dd, J=4.8, 9.5Hz), 2.45-2.30 (1H, m), 2.25 (1H, br. s), 2.15-2.00 (1H, m), 1 80-1 60 (1H, HCl salt:amorphous solid. IR(KBr). 3400, 1600cm⁻¹. Anal. Calcd for C₂₆H₂₉N₃O₂·HCl·H₂O C, 66 44; H, 6.86; N, 8.94 Found: C, 66.33, H, 7.16 N, 8.86.

EXAMPLE 15

[0392] Preparation of 4-{N-[2-(3-(S)Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaminol-N′-(2-chlorobenzyl)benzamide

[0393] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)benzoic acid and 2-chlorobenzylamine in 88% yield according to a procedure similar to that described in Example 1 (iii)

[0394]¹H NMR (270MHz, CDCl₃) δ7.68 (2H, d, J=9.2Hz), 7.50-7.20 (9H, m), 6.80 (2H, J=92Hz), 6.50-6.40 (1H, m), 5.13 (1H, dd, J=66, 8. Hz), 4.71 (2H, d, J=5.9Hz), 4.59 (1H, d, J=7.0Hz), 4 54 (1H, d, J=7.OHz), 4 22-4. 10 (1H, m), 3.29 (3H, s), 3.15-2.97 (2H, m), 2.87-2.80 (1H, m), 2.85 (3H, s), 2.75-2.52 (3H, m), 2.13-1.98 (1H, m), 1.35-1.70(1H, m)

EXAMPLE 16

[0395] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino}-N′-(2-chlorobenzyl)benzamide

[0396] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaxnino)-N′-(2-chlorobenzyl)benzamide in 98% yeid according to a procedure similar to that described in Example 2.

[0397]¹H NR (270MHz, free amine, CDC1₃) δ7.68 (2H, d, J=8.8Hz), 7.50-7.20 (9H, m). 6.79 (2H, d, J=8.8Hz), 6.50-6.40 (1H, m), 5.14 (1H, dd, J=6.0, 9.0Hz), 4.71 (2H, d, J=5.9Hz), 4.25-4.20 (1H, m), 3.12 (1H, dd, J=8.8, 12.8Hz), 3.03 (lH, dd, J=6.2, 12.8Hz), 2.95-2.80 (1H, m), 2.84 (3H, s), 2.72 (lH,d, J=9.9Hz), 2.56 (1H, dd, J=4.4, 9.9Hz), 2.40-2.32 (1, m), 2.162.00 (1H, m), 1.80-1.55 (2H, m) HCl salt:amorphous solid. IR(KBr): 3300, 1630, 1605cm⁻¹. Anal. Calcd for C₂₇H₃₀N₃O₂Cl·HCl·H₂O·0.3C₃H₈O C, 62.46; H, 6.65; N, 7.83 Found: C, 62.51; H, 7.02; N, 7.94.

EXAMPLE 17

[0398] Preparation of 4-{N-[2-(3-(S)-Methoxnnethoxprrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′,N′-dimethylbenzamide

[0399] This was prepared from 4-({ N-[2-(3-(S)-methoxymethoxypyrrolidin-1-y1)-1-(S)-phenylethyl]-N-methylamiino)benzoic acid and dimethylamine hydrochloride in 71% yield according to a procedure similar to that described in Example 1 (iii).

[0400]¹H NMR (270MHz, CDCl₃) δ7.50-7.20 (7H, m), 7.00-6.75 (2H, m), 5.35-5.25 (1H,m), 4.62 (1H, d, J=7.0Hz), 4.58 (1H, d, J=6.6Hz), 4.35-4.20 (1H, m), 3.40-3.20 (2H, m). 3.32 (3H, s), 3.15-3.30 (1K m), 3.07 (6H, s), 2.95-2.70 (2H, m), 2.81 (3H, s), 2.25-2.05 (1H,m), 2.00-1.80 (1H, m), 1.80-1.55 (1H, m)

EXAMPLE 18

[0401] Preparation of 4-{-[2-(3-(S)-Hydroxypyrrolidin-1-(S)-phenylethyl]-N-methylamino}-N′,N′-dimethylbenzamide

[0402] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N,N-dimethylbenzamide in 88% yield according to a procedure similar to that described in Example 2.

[0403]¹H NMR (270MHz, free amine, CDCl₃) δ7.37 (2H, d, J=8 8Hz), 7 35-7 20 (5H, m). 6.79 (2H, d, J=9.2Hz), 5.13 (1H,dd, J=6.0, 9.0Hz), 4.25-4.17 (1H, m), 3.18-2 98 (2H m), 3.07 (6H, s), 2.91 (1H, ddd, J=5.1, 8.4, 8 4Hz), 2.81 (3H, s), 2.74 (1H,d, J=9 2H.z), 2.55 (1H, dd, J=4.8, 9.5Hz), 2.37-2.25 (1H, m), 2.20-2.00 (1H, m), 1.80-1.55 (2H, m)

[0404] HCl salt:amorphous solid. IR(KBr) 3400, 1610cm⁻¹. Anal. Calcd for C₂₂H₂₉N₃O₂·HCl·H₂O: C, 62.62 H, 7.64; N,9.96 Found: C, 62.52; H, 7.86; N, 9.98.

EXAMPLE 19

[0405] Preparation of 4-{N-[1-(S)-Phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-methyl-N′-propylbenzamide

[0406] This was prepared from 2-R)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol in 32% over all yield according to a procedure similar to that described in Example 1 (i)(iii).

[0407]¹H NMR (270MHz, CDCl₃) δ7.40-7.20 (7H, m), 6.77 (2H, d, J=8.8Hz), 5.11 (1H, dd, J=7.0, 7.7Hz), 4.60-4.55 (0.6H, m), 4 534.47 (0.4H, m), 4.38-4 25 (1H, m), 3.90-3.75 (1H, m), 3.55-3.30 (3H, m), 3.15-2.92 (2H, m), 3 03 (3H, s), 2.81 (I 8H, s), 2 80 (1.2H, s), 2.80-2.70 (1H, m), 2.68-2.50 (3H, m), 2.15-1.95 (1H, m), l 90-1.45 (9H, m), 1.00-0.80 (3H, m).

EXAMPLE 20

[0408] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-methyl-N′-propylbenzamide

[0409] This was prepared from 4-{N-[1-(S)-phenyl-2-(3-(S)-tetranydropyran-2-yloxypyrrolidin-1-yl)ethyl]-N-methylamino} -N′-methyl-N′-propylbenzaniide in 83% yield according to a procedure similar to that described in Example 2.

[0410]¹H NMR (270MHz, free amine, CDCl₃) δ7.40-7.20 (7H, m), 6.79 (2H, d, J=8.8Hz), 5.11 (1H, dd, J=6.2, 8.8Hz), 4.28-4.16 (1H, m), 3.46-3.32 (2H, m), 3.18-2.98 (1H m), 3.03 (3H, s), 2.90 (1H, ddd, J=5.1, 8.4, 8.5Hz), 2.81 (3H, s), 2.78-2.70 (1H, m), 2.56 (1H, dd, J=4.6, 9.7Hz), 2.32 (1H, ddd, J=6.2, 9.2, 9.2Hz), 2.18-2.00 (1H, m), 1.90-1,50 (4H, m), 1.00-0.80 (3H,m) HCI salt:amorphous solid. IR(KBr): 3350, 1610cm⁻¹. Anal. Calcd for C₂₄H₃₃N₃O₂·HCl·0.75H₂O:C, 64.70; H 8.03; N,9.43 Found: C, 64.68; H, 8.39; N, 9.49.

EXAMPLE 21

[0411] Preparation of 3-{N-[2-(3S)-Methoxymethoxyprrolidin-1-yl)-1-(S)-phenvlethyl]-N-methylamino}-N′-propylbenzamide

[0412] (i) Methyl-3-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate

[0413] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 3-methylaminobenzoate in 78% yield according to a procedure similar to that described in Example 1 (i).

[0414]¹H NMR (270Mz, CDCl₃)δ7.51-7.48 (1H, m), 7.39-7.34 (1H, m), 7.33-7.20 (6H, m), 7.04-6.98 (1H, m), 5.15-5.05 (1H, m), 4.59 (1H, d, J=7.0Hz), 4.55 (1H, d, J=7.0Hz) 4.20-4.10 (1H, m), 3.89 (3H, s), 3.30 (3H, s), 3.15-2.97 (2H, m), 2.90-2.80 (1H, m), 2.82 (3H, s), 2.77-2.55 (3H, m), 2.12-1.98 (IRm), 1.83-1.60 (1H, m) ps (ii) 3-{-N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaminolbenzoic acid

[0415] This was prepared from methyl 3-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethy[I-N-methylamino)benzoate in 100% yield according to a procedure similar to that described in Example 1 (ii)

[0416]¹H I (270, CDCl₃) δ7.98 (1H, br s), 7 47 (1H, d, J=7 7Hz), 7.30-7 10 (6H, m), 6 82 (1H, d, J=2.2, 8.4Hz), 5.70-5 60 ( H, m), 4.63 (1H, d, J=6 6Hz), 4 59 (1H, d, J=6.6Hz), 4.40-4.30 (l1H, m), 4.04 (1H, br. s), 3.77 (1H, dd, J=5.9, 11.7Hz), 3.68-3.58 (1H, m), 3.48-3 28 (2H, m), 3 32 (3H, s), 3.12-3.00 (1H, m), 2.96-2.84 (1H, m), 2.71 (3H, s), 2.26-2.12 (1H, m), 2.06-1.92 (1H,m)

[0417] (iii) 3-{N-[2-(3-(S)-Methoxymethoxpyrrolidin-1- l)- -(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide

[0418] This was prepared from 3-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and n-propylarmine in 78% yield according to a procedure similar to that described in Example 1 (iii).

[0419]¹H NMR (270MHz, CDCl₃) δ7.34-7.19 (7H, m), 6.98 (1H, d, l=7 3Hz), 6 91 (1H, dd, J=2.2, 8.1Hz), 6.22 (1H, br. s), 5 16-506 (1H, m), 4.57 (1H, d, J=6.6Hz), 4 53 (1H, d, J=6.6Hz), 4.224.12 (1H, m), 3.46-3.32 (2H, m), 3.28 (3H, s), 3.16-2.96 (1H, m), 2.81 (3H, s), 2.86-2.52 (4H, m), 2.14-1.98 (lPm), 1 82-1.56 (4H, m), 0.98 (3H, t, J=7.3Hz)

EXAMPLE 22

[0420] Preparation of 3-{N-[2-(3-(S)-Hydroxypyrrolidin-1yl)-1-(S)-phenyiethyl]-N-methylamino}-N′-propylbenzamide

[0421] This was prepared from 3-(N-(2-(3-(S)-methoxymethoxypyrrolidin- 1-yl)-1-(S)-phenylethyl)-N-methylamino)-N′-propylbenzanide in 90% yield according to a procedure similar to that described in Example 2.

[0422]¹H NMR (270MHz, CDCl₃) δ7.42-7 37 (1H, m), 7.36-7.19 (6H m), 6.97 (1H, d, J=7.7Hz), 6.92 (1H, dd, J=2.6, 8.1Hz), 6 21 (1H, br s), 5.13 (1H, dd, J=5.9, 8.8Hz), 4.26-4.14 (1H, m), 3.48-3.32 (2H, m), 3 18-3 00 (2H, m), 2.92 (1H, ddd, J=4.8, 8.4, 8.4Hz), 2.86-2.72 (1H, m), 2.78 (3K s). 2.50 (1H, dd, J=4.8, 9.9Hz), 2.36-2.22 (1H, m), 2.20-2.02 (1H, m), 2.00-1.70 (2H,m). 1.63 (2H. ddd, J=7.3, 14.7, 14 7Hz), 0.93 (3H, t, J=7.3Hz) HCl salt:brown powder. mp. 105-114° C. IR(KBr) :3350, 1635cm⁻¹. MS m/z: 381(M⁺). Anal. Calcd for C₂₃H₃₁N₃O₂·HCl·0.7H₂O·0.3C₆H₁₄O:C,64.58, H, 8.22; N, 9.11 Found: C, 64.42; H,8.54; N, 9.34.

EXAMPLE 23

[0423] Preparation of 2-Chloro-4-{N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethyl]-N-methylamino}-N′-propylbenzamide (i) Methyl 2chloro-4-{N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoate

[0424] This was prepared from 2-(R)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(3 -(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and methyl 2-chloro4- methylaminobenzoate in 40% yield according to a procedure similar to that described in Example 1(i).

[0425]¹H NMR (270MHz, CDCl₃) δ7.86-7.80 (1I, m), 7.38-7.22 (SH, m), 6.83-6.78 (1H, m), 6.72-6.65 (1H, m), 5.10 (1H, dd, J=6.6, 7.7Hz), 4.604.55 (0.6H, m), 4,50-4.45 (0.4H, m), 4.38-4.22 (1H, m), 3.86 (31, s), 3.85-3.75 (K1, m), 3.50-3.37 (1H, m), 3.13-2.90 (3H, m), 2.85 (1.81, s), 2.84 (1.2H, s), 2.80-2.50 (3H, m), 2.20-1.95 (1H, m), 1.95-1.40 (7H, m).

[0426] (ii) 2-Chloro-4-{N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxpyrrolidin-1-yl)ethyl]-N-methblamino}benzoic acid

[0427] This was prepared from methyl 2-chloro-4-(N-{I-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin- 1 -yl)ethyl]-N-methylamino benzoate in 100% yield according to a procedure similar to that descnbed in Example 1 (ii).

[0428]¹H NMR (270MHZ, CDCl₃) δ7.86-7.75 (1H, m), 7.38-7.22 (5H, m), 6.80-6.60 (2H, m), 5.20-5.10 (1H, m), 4.60-4.55 (0 6H, m), 4 504 45 (0.4H, m), 4.38-4.22 (1H, m), 3.85-3.37 (3H, m), 3.20-3.00 (2H, m), 2 80-2.50 (4H, m), 2.69 (3H, s), 2.20-1.95 (1H, m), 1.95-1.40 (7H, m).

[0429] (iii) 2-Chloro-{4-N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)-ethyl-N-methylamino}-N′-propylbenzamide

[0430] This was prepared from 2-chloro-4-{1N-[1-(S)-phenyl-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethyl]-N-methylamino}benzoic acid and n-propylamine in 68% yield according to a procedure similar to that described in Example 1 (iii).

[0431]¹H NMR (270MHz, CDCl₃) δ7.78-7.72 (1H, m), 7.38-7 22 (5H, m), 6.79-6.70 (2H, m), 6.60-6.48 (1H, m), 5.07 (1H, dd, J=6.6, 7.3Hz), 4.60-4.55 (0.6H, m), 4.50-4.45 (0.4H, m), 4.38-4.22 (1H, m), 3.90-3.75 (1H, m), 3.50-3.37 (3H, m), 3.13-2.90 (2H, m), 2.82 (3H, s), 2.80-2.50 (4H, m), 2.20-1.95 (1H, m), 1.95-1.40 (9H, m), 0.99 (3H, t, J=7.3Hz).

EXAMPLE 24

[0432] Preparation of 2-Chloro-4-N-(2-(3-(S)-hydroxypyrolidin-I -yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide

[0433] This was prepared from 2-chloro4-{N-(1-S)phenyl-2-3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide in 89% yield according to a procedure similar to that described in Example 2.

[0434]¹H NNR (270MHz, free amine, CDC[₃) 6 7.76 (1H, d, J=8.8Hz), 7.40-7 20 (5H, m), 6.75 (1H, dd, J=2.6, 8.8Hz), 6.72 (1H, d, J=2.6Hz), 6.54 (1H, br. s), 5.07 (1H, dd, J=5.9, 92Hz), 4.30-4.20 (1H, m), 3.46-3.35 (2H, m), 3.12 (1H, dd, J=9.2, 12.8Hz), 3.01 (IF, dd, J=6.0, 13.0Hz), 2.95-2.78 (1H, m), 2.83 (3H, s), 2.72 (1H, d, J=9.9Hz), 2.58 (1H, dd, J=4.8, 9.5Hz), 2.35 (1H, ddd, J=6.0, 8.9, 9 OHz), 2 18-2.00 (1H, m), 1.90-1.50 (4H, m), 0.99(3H, t, J=7.7Hz) HCl salt:amorphous solid. IR(KBr): 3350, 1600cm⁻¹. Anal. Calcd for CztH₃₀N₃0₂Cl HC1 0.2HZO C, 60 58, H, 6.94; N, 9.21 Found:C,60.29;H,7.13 ;N,9.13

EXAMPLE 25

[0435] Preparation of 2-Methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide (i) Methyl 2-methoxv-4- fN-f2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate

[0436] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3 -(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 2-methoxy4-methylaminobenzoate in 41% yield according to a procedure similar to that described in Example 1 (i).

[0437]¹H NMR (270MHz, CDCl₃) δ7.79 (1H, d, J=9.2Hz), 7.36-7.20 (5H, m), 6.40 (1H, dd, J=2.4, 8.9Hz), 6.27 (1H, d, J=2.6Hz), 5.13 (1H, dd, J=7.0, 8.1Hz), 4.60 (1H, d, J=7.0Hz), 4.56 (1H, d, J=6.6Hz), 4.25-4.15 (1H,m), 3.86 (3H, s), 3.82 (3H, s), 3.30 (3H, s), 3.14-2.96 (2H, m), 2.37 (3H, s), 2.90-2.80 (1K m), 2.78-2.52 (3H, m), 2.14-1.96 (1I-L m), 1.84-1.70 (1H, m)

[0438] (ii) 2-Methoxv-4-IN-r2-(3-(S)-methoxymethoxvvrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid

[0439] This was prepared from methyl 2-methoxy-4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl3-N-methylamino}benzoate in 100% yield according to a procedure similar to that described in Example 1 (ii).

[0440]¹H NMR (270MHz, CDCl₃) 6 7.98 (1H, d, J=8.8Hz), 7.38-7.16 (51 m), 6.54 (1H, dd, J=2.4, 9.0Hz), 6.35-6.25 (lm), 5.20-5.05 (1H, m), 4.60 (1H, d, J=7.0Hz), 4.56 (1H, d, J=7.0Hz), 4.254.15 (1H,m), 3.99 (3EI, s), 3.30 (3H, s), 3.14-3.05 (2H, m), 2.91 (31, s), 2.90-2.52 (4H, m), 2.14-2.00 (1H, m), 1.90-1.70 (1H, m),

[0441] (iii) 2-Methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino]-N′-propylbenzamide

[0442] This was prepared from 2-methoxy-4-{N-(2-(³-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and n-propylamine in 84% yield according to a procedure similar to that described in Example 1 (iii).

[0443]¹H NMR (270MHz. CDC]₃) 6 8 07 (1H, d, J=8.8Hz), 7.78-7.68 (1H, m),7.36-7.20 (5H, m), 6 51 (1H, dd, J=2 4, 9 OHz), 6 27 (1H, d, J=2.2Hz), 5.11 (1H, dd, J=66, 81Hz), 4.60 (1H, d, J=7.0Hz), 4.56 (1H, d, J=6 6Hz), 4 25-4 15 (1H,m), 3.89 (3H s), 3.45-3.35 (2H, m), 3 30 (3H, s), 3 14-2 96 (2H, m), 2.86 (3H, s), 2 90-2 80 (1H, m), 2.78-2.52 (3H, m), 2.14-1 96 (1H, m), 1 84-1.70 (1H, m), 1.68-1.50 (2H, m), 0.97 (3H, t, J=7.3Hz)

Example 26

[0444] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino}-2-methoxy-N′-propylbenzamide

[0445] This was prepared from 2-methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)-N′-propylbenzamide in 85% yield according to a procedure similar to that described in Example 2.

[0446]¹H NMR (270MHz free amnine, CDCl₃) δ8.07 (1H, d, J=8.8Hz), 7.78-7.68 (1H, m), 7.38-7.22 (5H, m), 6.53 (1H, dd, J=2.2, S.8Hz), 6.27 (1H, d, J=2.2Hz), 5.13 (1H, dd, J=6.2, 8.4Hz), 4.304.20 (1H,m), 3.89 (3H, s), 3.45-3.35 (2H, m), 3.20-3.00 (2H, m), 2.95-2.80 (1H, m), 2.85 (3H, s), 2.74 (1H,d, J=9 5Hz), 2.58 (1H, dd, J=4.8, 9.5 SHz), 2.40-2.27 (1H, m), 2.18-2.02 (1H, m), 1.95- 1.55 (4H, m), 0.97 (3H, t, J=7.3Hz) HCl salt:amorphous solid. IR(KBr): 3400, 1600cm⁻¹. Anal. Calcd for C₂₄H₃₃N₃O₃·HCl·0.8CH₄O: C, 62.89; H, 7.92; N, 8.87 Found: C, 63.16 H, 8.32; N, 9.20

EXAMPLE 27

[0447] Preparation of 3-Methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide (i) Methyl 3-methoxy-4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate

[0448] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 3-methoxy-4-methylaminobenzoate in 60% yield according to a procedure similar to that described in Example 1 (i).

[0449]¹H NMR (270MHz, CDCl₃) δ7.58-7.53 (2H, m), 7.31-7.20 (SH, m), 6.71 (1H, d, J=8.4Hz), 5.13 (1H, t, J=7.3Hz), 4.59 (1H. d, J=7.0Hz), 4.55 (1H, d, J=7.0Hz), 4.15-4.05 (1H,m), 3.95 (3H, s), 3.89 (3H, s), 3.30 (3H, s), 3 09 (2H, d, J=7.3Hz), 2.87 (1H, dd, J=6.2, 9.9Hz), 2.60 (3H, s), 2.60-2.52 (2H, m), 2.47 (1H, dd, J=4.0, 9.9Hz), 2.08-1.92 (1H, m), 1.73-1.60 (1H, m)

[0450] (ii) 3-Methoxy-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid

[0451] This was prepared from methyl 3-methoxy4-{N-12-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyll-N-methylamino}benzoate in 100% yield according to a procedure similar to that described in Example 1 (ii).

[0452]¹H NMR (270MHz, CDC1₃) 8 7.52-7.45(2H, m), 7.32-7.12 (5H, m), 6.65 (1H, d, J=8.4Hz), 5.47 (1H, dd, J=6.6, 7.0Hz), 4.64 (1H, d, J=7.0Hz), 4.60 (1H, d, J=6.6Hz), 4.45-4.35 (1H,m), 4.02 (3H, s), 3.85-3.70 (3H, m), 3.68-3.57 (1H, m), 3.32 (3K, s), 3.30-3.05 (2H, m), 2.64 (3H, s), 2.40-2.23 (1H, m), 2.15-2.00 (1H, m)

[0453] (iii) 3 -Methoxy4- N-f243-(S)-methogNethoxayrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaminol-N′-propylbenzamide

[0454] This was prepared from 3-methoxy 4{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-y[)-1-(S)-phenylethyl]-N-methytamino}benzoic acid and n-propylanine in 64% yield according to a procedure similar to that described in Example 1 (iii).

[0455]¹H NM(270MHz, CDC1₃) 8 7.45 (1H, d, J=1.8Hz), 7.32-7.18 (5H, m), 7.11 (1H, dd, J=1.8,8.4Hz), 6.66 (1H, d, J=8.1Hz), 6.15-6.05 (1H,m), 5.03 (1H,t, J=7.7Hz), 4.59 (1H, d, J=7.0Hz), 4.54 (1H, d, J=7.0Hz), 4 154.05 (1H,m), 3.96 (3H, s), 3.45-3.35 (2H, m), 3.30 (3H, s), 3.08 (2H, d, J=7.7Hz), 2.95-2.85 (1H, m), 2.65-2.50 (2H, m), 2.57 (3H, s), 2.46 (1H, dd, J=4.4, 9.9Hz), 2.10-1.90 (1H, m), 1.75-1.55 (3H, m), 0.99 (3H, t, J=7.3Hz)

EXAMPLE 28

[0456] Preparation of 4-{N-[2-(3-S)-Hydroxypyrrolidin-1-yl)-1-(S)-2phenyiethyl]-N-methylamino}-3-methoxy-N′-propylbenzamide

[0457] This was prepared from 3-methoxy-4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylarruno}-N′-propylbenzamide in 77% yield according to a procedure similar to that described in Example 2.

[0458]¹H NMR (270MHz, free amine, CDCl₃) δ7.48 (1H, d, J=2.2Hz), 7.37-7.22 (SH, m) 7.12 (1H, dd, J=2.2, 8.4Hz), 6.72 (1H, d, J=8.4Hz), 6.15-6.05 (1H,m), 5.16 (1H, dd, J=6.6, 8.8Hz), 4.15-4.05 (1H,m), 3.97 (3H, s), 3.45-3.35 (2H, m), 3.23 (2H, dd, J=8.8, 12.5Hz), 2.99 (1H, dd, J=6.4, 12.3Hz), 2.80-2.70 (1H, m), 2.59 (3H, s), 2.45 (1H, dd, J=4.4, 9.9Hz), 2.20-1.90 (2H, m), 1.75-1.40 (4H, m), 0.99 (3H, t, J=7.3Hz) HCl salt: amorphous solid. IR(KBr): 3350,1630cm⁻¹.

EXAMPLE 29

[0459] Preparation of 3-chloro4{N-[2-(3-(S)methoxymethoxpyrroidin-1-yl)-1-(S)-phenylethyl]-N-methylaminol-N′-propylbenzamide (i) 3-chloro4-(N-f2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethy]-N-methylamino}benzonitrile

[0460] To a stirred solution of the mixture of 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol (251 mg, 1.00mrnol) and triethylamine (0.167 ml, 1.20 mmol) in CH₂Cl₂(4 ml) was added methanesulfonyl chloride (0.093 ml, 1.20mmoi) dropwise at 0° C. (ice bath). After 15.5 h stirring at room temperature, the reaction mixture was washed with saturated NaHCO₃ aqueous solution, brine, dried (Na₂SO₄), and concentrated to give 238 mg of brown viscous oil-(i). To a suspension of NaH (48 mg, 1.20 mmol) in N,N-dimethylformamide (2 ml) was added a solution of 3-chioro-4-methylaminobenzoniinie (200 mg, 1.20mmoi) at room temperature. After stirring for 45min, to this mixture was added a solution of the above brown viscous oil-(i) in N,N-dimethylformamide (2 ml) at room temperature and the mixture was stirred at room temperature for 4.5 h. H₂O was added to this mixture, basified with 25%-,THOH and extracted %with CH₂Cl₂. The extract was washed with water, brine, dried (Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel 20 g, CH₂Cl₂/MeOH 100/1-50/1) to afford 244 mg (61%) of brown oil.

[0461]¹H NMR (270M z, CDCl₃) δ7.61 (Il d, J=2.2Hz), 7.43-7.25 (6H, m), 6.98 (1H, d, J=8.4Hz), 5.03 (1H, dd, J=7.3, 7.7Hz), 4.58 (1H, d, J=6.6Hz), 4.54 (1H, d, J=6.6Hz), 4.10-3.97 (1H,m), 3.31 (3H, s), 3.10 (2H, dd, J=1.5, 7.7Hz), 2.75-2.65 (1H, m), 2.69 (3H, s), 2.55-2.43 (3H, m), 2.03-1.85 (1H, m), 1.70-1.60 (1H, m)

[0462] (ii) 3-Chloro-4-{N[2-(3-(S)methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide

[0463] To a suspension of t-BuOK (381 mg, 3.05 mmol) and H₂O (0.055 ml, 3.05 mmol) in t-BuOH (1.0 ml) was added a solution of 3-chloro4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaamino}benzonitrile (244 mg, 0.611 mmol) in t-BuOH (1.0 ml) at room temperature. After refluxino for 0.5 h, the mixture was allowed to cool to room temperature. ni-Propyliodide (0.298 ml, 3.05 mmol) was added to the mixture, and the mixture was refluxed for 3 h. After cooling down to room temperature, the solvent was evaporated. The residue was dissolved in CH₂Cl₂ and washed with water and brine, dried (Na₂SO₄), and concentrated to give pale brown oil, which was punfied by column chromatography (silice gel, 15 g, CH₂Cl₂/MeOH: 80/1-50/1) to give 206 mg (73%) of ivory amorphous.

[0464]¹H N (270MHz CDCl₃) δ7.77 (1H, d, J=2.2Hz), 7.52 (1H,dd, J=2.2, 3 4Hz), 7.36-7.20 (SF, m), 6.92 (1H, d, J=8.4Hz), 6.15-6.00 (1H,m), 4.91 (1H, dd, J=7.3 7.7Hz), 4.57 (1H, d, J=7.0Hz), 4.53 (1H, d, J=7.0Hz), 4.10-3.98 (1H,m), 3.45-3.35 (2H, m), 3.29 (3H, s), 3.14 (1H, dd, J=7.7, 12.5Hz), 3.05 (1H dd, J=7.3, 12.5Hz), 2.73 (1H, dd, J=6.2, 9.9Hz), 2.64 (3H, s), 2.55-2.43 (3H, m), 2.05-1.88 (1H, m), 1.75-1.55 (3H, m), 0.96 (3H, t, J=7.3Hz).

EXAMPLE 30

[0465] Preparation of 3-Chloro4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}N′-2propylbenzamide

[0466] This was prepared from 3-chloro-4-{N-[2-(3-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide in 96% yield according to a procedure similar to that described in Example 2.

[0467]¹H NNM (270MHz, free anune, CDCl₃) δ7.81 (1H, d, J=2.2Hz), 7.51 (1H,dd. J=2.2, 8.4Hz), 7.42-7.22 (5H, m), 6.93 (1H, d, J=84Hz), 6.15-600 (1H,m), 499 (1H, dd, J=7.3, 7.9Hz), 4.204.05 (1H,m), 3.45-3.35 (2H, m), 3.16 (1H, dd, J=7.7, 12.5Hz), 3.08 (114, dd, J=7.3, 12.5Hz), 2.75-2 60 (2H, m), 2.65 (3H, s), 2.41 (1H, dd, J=4.4, 9.5Hz), 2.25-2.15 (1H, m), 2.08-1.93 (1H, m), 1.90-1.40 (4H, m), 0.99 (3H, t, J=7.3Hz). Fumaric acid salt:amorphous solid. IR(KBr): 3350, 1630cm⁻¹. MS m/z: 416, 418 (M+H)⁺. Anal. Calcd for C₂₃ N₃₀N₃O₂Cl·C₄H₄O₄H₂O: C, 58.96; H, 6.60; N, 7.64 Found : C, 59.35 ; H,6.64; N, 7.55.

EXAMPLE 31

[0468] Preparation of 6-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyiamino}-N′-propylnicotinamide (i) Methyl 6-{N-[2-(3-(S)-methoxymethoxpyrrolidinl-1-yl)-1-(S)-phenylethyl]-N-methylamino}nicotinate

[0469] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 6-methylamiinonicotinate in 60% yield according to a procedure similar to that described in Example 29 (i).

[0470]¹H NMR (270MHz, CDCl₃) δ8.83 (1H, d, J=2.2Hz), 8.01 (1H, dd, J=2.2, 9.2Hz), 7.35-7.20 (5H, m), 6.48 (1H, d, J=9.2Hz), 6.44-6.32 (1H, m), 4.59 (1H, d, J=7.0 Hz). 4.56 (1H, d, J=6.6Hz), 4.22-4.12 (}H, m), 3.86 (3H, s), 3.30 (3H, s), 3.17-2.97 (3H, m), 2.83 (3H, s), 2.80-2.70 (1H, m). 2 65-2 50 (2H, m), 2.12-1 95 (1H, m), 1.80-1.65 (1H, m). (ii) 6-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}nicotinic acid

[0471] This was prepared from methyl 6-{(N-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}nicotinate in 100% yield according to a procedure similar to that described in Example 1 (ii).

[0472]¹H NMR(270M~z, CDC1₃) 8 8.80-8.75 (1H, m), 7 95-7 87 (1H, m), 7.35-7 15 (5H, rn) 6.57 (1H, br.s), 6.42 (1H, d, J=9.2Hz), 4.62 (1H,d, J=6.6Hz), 4 59 (1H, d, J=7.0Hz), 4.35-4.00 (2H, m), 3.50-3.25 (2H, m), 3.32 (3H, s), 3.18-3.08 (1H, m), 3.02-2.70 (3H, m), 2.79 (3H, s), 2.20-2.05 (1H, m), 1.90-1.80 (1H, m).

[0473] (iii) 6-{N-[2-(3-(S)-Methoxymethoxpyrrolidin-1-yl)-]-(S)-phenylethyl]-N-methylamino}-N′-propylnicotinamide

[0474] This was prepared from 6-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}nicotinic acid and n-propylamine in 65% yield according to a procedure similar to that described in Example 1 (iii).

[0475]¹H NMR (270MHz, CDCl₃) δ8.57 (1H d, J=2.6Hz), 7.89 (1H, dd, J=2.6, 9.2Hz), 7.35-7.20 (SH, m), 6.50 (1H, d, J=9.2Hz), 6.40-6.35 (1H, m), 6.00-5.90 (1H, m), 4.59 (1H d, J=7.0Hz), 4.56 (1lH d, J=7.0Hz), 4.20I4.10 (1H, mr), 3.45-3.35 (2H, m), 3.30 (3H, s), 3.17-2.92 (3H, m), 2.82 (3H, s)280-o2Q(1H, m), 2.65-2.50 (ZR, m), 2.12-1.95 (1H, m), 1.80-1.55 (3H, m), 0.99 (3H, t, J=7.3Hz).

EXAMPLE 32

[0476] Preparation of 6{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenyiethyl]-N-methylamino}-N′-propylnicotinamide

[0477] This was prepared from 6-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)-N′-propylnicotinrnide in 73% yield according to a procedure sinilar to that described in Example 2.

[0478]¹H NM (270MHz, free amine, CDCl₃) δ8.58 (1H, d, J=2.6Hz), 7.89 (1H, dd, J=2.6, 8.8Hz), 7.35-7.20 (1H, m), 6.50 (1H, d, J=9 5Hz), 6 36 (1H, dd, J=5.9, 9.9Hz), 6.00-5.92 (1H, m), 4.254.15 (1H, m), 3 45-3 35 (2H, m), 3.17 (1H, dd, J=9.9, 12.5Hz), 3.05-2.95 (2H, m), 2.81 (3H, s), 2.72 (1H, d, J=9.5Hz), 2.62 (1H, dd, J=4.8, 9.9Hz), 2.40-2.25 (1H, m), 2.17-2.02 (IR, m), 1.95-1.75 (2H, m), 1.70-1.55 (2H, m), 0.98 (3H, t, J=7.3Hz).

[0479] Fumaric acid salt:amorphous solid. IR(KBr): 3350, 1630cm⁻¹. MS m/z: 383(M+H)⁺. Anal. Calcd for C₂₂H₃₀N₄O₂·C₄H₄O₄·1.5H₂O: C, 59.42; H, 7.10; N, 10.66 Found. C, 59.50; H, 7.43; N, 10.73.

EXAMPLE 33

[0480] Preparation of 4{N-[1-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylaminl}-N′-propylbenzamide (i) Methyl 4-{N-[1-(S)-(3-methoxyyethoxyphenyl)-2-(3-(S)-methoxymethoxMprrolidin-1 -v5-ethyll-N-methylamino}benzoate

[0481] This was prepared from the mixture of 2-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and I -(S)-(3-metboxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrroldin-1-yl)ethanol and methyl 4-methylaminobenzoate in 60% yield according to a procedure similar to that described in Example 1 (i).

[0482]¹H NMR (270Mz, CDCl₃) δ7.89 (2H, d, J=9.2Hz), 7.27-7.19 (1H, m), 6.98-6.88 (3H, m), 6.77 (2H, d, J=9.2Hz), 5.14 (2H, s), 5.14-5.08 (1H, m), 4.59 (1H, d, J=6.6Hz), 4.55 (1H, d, J=7.0Hz), 4.22-4.12(1H, m), 3.85 (3H s), 3.46 (3H, s), 3 30 (3H, s), 3.04 (2H, d, J=8.1Hz), 2.88 (3H, s), 2.85-2.53 (4H, m), 2.10-1.98 (1H, m), 1.83-1.70 (1H, m).

[0483] (ii) 4-{N-1-(S)-(3-Methog ethoxhrnyl)2-(3-fS)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylaminolbenzoic acid

[0484] This was prepared from methyl 4-(N-[1-(S)-(3-methoxymethoxyphenyt)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoate in 100% yteld according to a procedure similar to that described in Example 1(ii).

[0485]¹H NMR (270MHz, CDCl₃) δ7.88 (2H, d, J=8.8Hz), 7.30-7.12 (1H, m), 6.98-6.84 (3H, m), 6.68 (2H, d, J=8.8Hz), 5.15-5.05 (1H, m), 5.10 (2H, s), 4.55 (1H, d, J=6.6Hz), 4.51 (1H, d, J=7.0Hz), 4.18-4 08 (1H, m), 3.42 (3H, s), 3.25 (3H, s), 3.10-2.92 (2H, m), 2.85 (1H, dd, J=6.4, 9 9Hz), 2.74 (3H, s), 2.70-2.53 (3H, m), 2.10-1.93 (1H, m), 1.80-1.65 (1H, m).

[0486] (iii) 4-{N-[1-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxynethoxypyrrolidin-1-yl)-ethyl]-N-methylamino I -N′-propylbenzamide

[0487] This was prepared from 4-({N-[1-(S)-(3-methoxymethoxyphenyl)-2-(-3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoic acid and n-propylamine in 80% yield according to a procedure similar to that described in Exarmple 1 (iii).

[0488]¹H NMI (270MHZ, CDCl₃) 6 7.65 (2H, d, J=9.2Hz), 7.28-7.18 (1H, m), 6.98-6.88 (3H, m), 6.76 (2H, d, J=8.8Hz), 6.05-5.90 (1H, m), 5.14 (2H, s), 5.08 (1H, dd, J=7.0, 7.7Hz), 4.59 (1H, d, J=6.6Hz), 4.55 (I1 d, J=7.0Hz), 4.224.12 (1H, mn), 3 46 (3H, s), 3.45-3.35 (2H, m), 3.30 (3H, s), 3.03 (2H, d, J=7.7Hz), 2.86 (3H, s), 2.85-2.80 (1H, m), 2.75-2.50 (3H, m), 2.12-1.95 (1H, m), 1.85-1.52 (3H, m), 0.97 (3H, t, J=7.3Hz)

EXAMPLE 34

[0489] Preparation of 4-{N-[1-(S)-(3-Hydroxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl,)-ethyl]-N-methylamino}-N′-propylbenzamide

[0490] This was prepared from 4-{N-[1-(S)(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino)-N′-propylbenzamide in 97% yield according to a procedure similar to that described in Example 2.

[0491]¹H NMR (270MHz, free amine, CDCl₃-DMSO-d6) δ8.85 (1H, br s), 7.69 (2H, d, J=9.2Hz), 7.11 (1H, J=7.7Hz), 6.98-6.90 (1H, m), 6.82-6.68 (SH, m), 5.06 (1H, dd, J=6.2, 8.4Hz), 4.30-4.18 (1H, m), 3.67 (1H, br.s), 3.40-3.30 (2H, m), 3.15-2.95 (2H, m), 2.86 (3H, s), 2.85-2.67 (2H, m), 2.63-2.56 (1H, m), 2.55-2.43 (1H, m), 2.15-1.98 (1H, m), 1.70-1.52 (3H, m), 0.96 (3H, t, J=7.3Hz). HCl salt:amorphous solid. IR(KBr) 3350, 1610cm⁻¹. MS m/z: 397(M⁺) Anal. Calcd for C₂₃H₃₁N₃0,-HC1I2.3H₂O C, 58.11; H, 7.76; N, 8.84 Found: C,57.82, H,8.06; N, 9.24

EXAMPLE 35

[0492] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-(3-methoxyphenyl)-ethyl]-N-methylamino}-N′-prropylbenzamide

[0493] To a solution of 4-{N-[ I -(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide (100 mg. 0.252 mmol) in MeOH (0.1 ml)—CH₃CN (0.9 ml) was added N,N-diisopropylethylamine (0.0641 ml, 0.353 mmol) and 10%-trimethylsilyl-diazomethane in CH₂Cl₂ (0.6 ml) at room temperature. After stirring for 22 h at room temperature, 25% —NH₄OH was added to the mixture and extracted with CH₂Cl₂. The extract was washed with brine, dried (Na₂SO₄) and concentrated to give brown oil, which was purified by column chromato-graphy (silica gel 5 g, CH₂Cl₂/MeOH: 30/1-10/1) to afford 55.2 mg (53%) of white amorphous.

[0494]¹H NM (270Mz free amine, CDCl₃) δ7.65 (2H, d, J=8 8Hz), 7.24 (1H, t, J=7.7Hz), 6.90-6.77 (5K, m), 6.05-5.90 (I H, m), 5.10 (lEL dd, J=5.9, 8.8Hz), 4 254.18 (1H, m), 3.77 (3H, s), 3.45-3.35 (2H, m), 3.11 (1H, dd, J=9.2, 12 8Hz), 3.01 (1H, dd, J=5.9, 12.8Hz), 2.95-2.80 (1H, m), 2.84 (3H, s), 2 72 (lK d, J=9 5Hz), 2.56 (1H, dd, J=4.8, 9.5Hz), 2.38-2.25 (1H, m), 2.16-2.00 (1H, m), 1.85-155 (4H, m), 097 (3H, t, J=7.7Hz). HCl salt:amorphous solid. 1R(neat, free amine): 3350, 1610cm⁻¹. MS m/z: 412(M+H)⁺. Anal. Calcd for C₂₄H₃₃N₃O₃-HCl0.5H₂O C, 63.08; H, 7.72; N, 9.19 Found:C,62.89 H, 7.77; N, 9.25.

EXAMPLE 36

[0495] Preparation of 4-{N-[1-(S)-(3-t-Butoxycarbonylmethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)ethyl]-N-methylaminop-N′-propylbenzamide

[0496] A mixture of 4-(N-[[1-(S)-(3-hydroxyphenyt)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamnino)-NM-propylbenzamide (100 mg, 0.252 mmol), t-butyl bromoacetate (0.0409 ml, 0 277mmot) and K₂CO₃ (38.3 mg, 0.277mmol) in DMF (1.5 ml) was stirred at room temperature for 2 h. H₂O was added to the mixture and extracted with AcOEt/toluene=211. The extract was washed with water, brine, dried (Na₂SO₄) and concentrated to give pale brown amorphous, which was purified by column chromato-graphy (silica gel 6 g, CH₂Cl₂/MeOH: 30/1-10/1) to afford 80.1 mg (62%) of white amorphous.

[0497]¹H NMR (270MHz, CDCl₃) δ7.65 (2H, d, J=9.2L), 7.23 (1H, t, J=7.7Hz), 6.94-6.86 (2H, m), 6.82-6.72 (3H, m), 6.05-5.90 (1H, m), 5.09 (1H, dd, J=6 2, 8 8Hz), 4 48 (¹H, s), 4.25-4.18 (1H, m), 3.45-3.35 (2H, m), 3.09 (1H, dd, J=9.2, 12.8Hz), 3.00 (1H, dd, J=5.9, 12.8Hz), 2.95-2.80 (1H, m), 2.83 (3H, s), 2.71 (1H, d, J=9.5Hz), 2.54 (1H, dd, J32 4.8, 9.5Hz), 2.38-2.25 (1H, m), 2.16-2.00 (1H, m), 1.85-1.50 (4H, m), 1.46 (9H, s), 0.98 (3H, t, J=7.3MHz).

EXAMPLE 37

[0498] Preparation of 4-{N-[1-(S)-(3-Carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylaminol-N′-propylbenzamide

[0499] A solution of 4-{N-(1-(S)(3-t-butoxycarbonylimethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino)-N′-propylbenzamnide (80.1 mg, 0.157 mmol) in trifluoroacetic acid (Imi) and CH₂Cl₂ (0.5 ml) was stirred at room temperature for 1.5 h. The solvent was evaporated. The residue was dissolved ;r CH₂Cl₂ and 1.0 M hydrogen chloride solution in diethyl ether (Imi) was added. The white powder wae collected and washed with Et₂O and dried under reduced pressure for 6.5 h at 45° C. to afford 86.2 mg (quant) of white powder.

[0500] HCl salt:white powder. ¹H NMR (270MHz, CDCl₃-DMSO-d6) δ12.49 (1H, br. s), 7.79 (2H, d, J=8.4Hz), 7.42 (1H, br. s), 7.23 (1H, t, J=7.7Hz), 7.07 (2H, d, J=8.4Hz), 6.85-6.76 (3H, m), 5.95-5.30 (1H, m), 4.53 (2H, s), 4.50-4.40 (1H, m), 4 00-3.70 (4H, m), 3 50-2.50 (3H, m), 2.80 (3H, s), 2.50-2.00 (2H, m), 1.75-1.55 (4H, m), 0.96 (3H, t, J=7.3Hz). IR(KBr): 3400, 1730, 1610cm⁻¹. MS rn/z: 456(M+H)⁺. mp. 108-110° C. Anal. Calcd for C₂₅H₃₃N₃O₅·HCl·3.5H₂O C, 54.10; H, 7.45; N, 7.57 Found: C, 54.07; H, 7 49; N, 7.39

EXAMPLE 38

[0501] Preparation of 4-{N-[1-(S)-Phenyl-2-pyrrolidin-1-yl)ethyl]-N-methylamino}-N′-propylbenzamide. (i) Methyl 4- {N-[1-(S)-phenyl-2-(pyrrolidin-1-ylethyl]-N-methylamino}benzoate

[0502] This was prepared from the mixture of 2-(R)-phenyl-2-(pyrrolidin-1-yl)ethanol and 1-(S)-phenyl-2-(pyrrolidin-1-yl)ethanol and methyl 4-methylaminobenzoate in 52% yield according to a procedure similar to that described in Example 1 (i).

[0503]¹H NM (270MHz, CDCl₃) δ7.88 (2H, d, J=9.2Hz), 7.38-7.20 (5H, in), 6.78 (2H, d, J=9.2Hz), 5.17 (IEI, t, J=7.3Hz), 3.84 (3H, s), 3.04 (2H. d, J=7.3Hz), 2.86 (3, s), 2.65-2.45 (4H, m), 1.80-1.65 (4H, m)

[0504] (ii) 4-{N[1-(S)-Phenyl-2-(pyrrolidin-1-vifethyl]-N-methylamino}benzoic acid

[0505] This was prepared from methyl 4-(N-[1-(S)-phenyl-2-(pyrrofidin-1-yl)ethyl]-N-methylamino}benzoate in 100% yield according to a procedure similar to that described in Example 1 (ii).

[0506]¹H NMR (270MHz, CDCl₃-DMSO-d6) δ7.92 (2H, d, J=8.8Hz), 7 38-7.20 (5H, m), 7.02 (2H, d, J=8.8Hz), 5,80 (fH, br.s), 4.00-3.00 (7H, m), 2.85 (3H, s), 2.20-1.90 (4H, m)

[0507] (ii) 4-{N-[1-(S)-Phenyl-2-(pyrrolidin-1-yl)ethyl]-N-methylamino}-N′-propylbenzamide

[0508] This was prepared from 4-{N-[1-(S)-phenyl-2-(pyrrolidin-1-yl)ethyl]-N-methylamino}benzoic acid and n-propylamine in 56% yield according to a procedure similar to that described in Exanple 1 (iii).

[0509]¹H NMR (270MHz, free amine CDCl₃) δ7.65 (2Hl, d, J=8.8Hz), 7.36-7.20 (5H, m), 6.79 (2H, d, J=8.8Hz); 6.05-5.90 (1H, m), 5.14 (1H, t, J=7.0Hz). 3 45-3.35 (2H, m), 3.04 (2H, d, J=7.0Hz), 2.84 (3H, s), 2.65-2.45 (4H, m), 1.75-1.50 (61 m), 0.97 (3H, t, J=7.3Hz). HCl salt:amorphous solid. 1R(KBr): 1610cm⁻¹. MS m/z: 366(M+H)⁺. Anal. Calcd for C₂₃H₃N₃O·HCl·0.5H₂O: C, 67.22; H, 8.09; N, 10.22 Found C, 6748, H, 8.37; N, 1032.

EXAMPLE 39

[0510] Preparation of 4-{N-f2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino}-N′-propyliphthalimide

[0511] This was prepared from 2-(R)-phenyt-2-(3-(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and I -(S)-phenyl-2-(3 -(S)-tetrahydropyran-2-yloxypyrrolidin-1-yl)ethanol and 4-methylamino-N′-propylphthalimide in 16% over all yield according to a procedure similar to that described in Example 1 (i) and 2.

[0512]¹H NMR (270MHz, free amine, CDC1₃) 8 7.63 (1H, d, J=8.4Hz), 7.38-7.22 (6H, m), 6.94 (1H, dd, J=2.6, 8.4Hz), 5.19 (1H, dd, J=5.9, 9.5Hz), 4.30-4.20 (1H, m), 3.59 (2H, t, J=7.3Hz), 3.18 (1H, dd, J=9.5, 13.2Hz), 3.03 (11, dd, J=5.5, 12.8Hz), 2.95 (3H, s), 2.95-2.85 (1H, m), 2.71 (1H, d, J=9.2Hz), 2.61 (1H, dd, J=4.8, 9.5Hz), 2.37 (1H, ddd, J=5.9, 8.8, 8.8Hz), 2.20-2.05 (1H, m), 1.75-1.60 (4H,m), 0.93 (3H, t, J=7.3Hz) HCl salt:amorphous solid. 1RP(KBr) 3400, 1760, 1700, 1620cm ⁻¹. Anal. Calcd for C₂₄H₂₉N₃O₃·HCl·0.5H₂O:C, 63.64; H,6.90; N, 9.28 Found: C,63-99; H, 7.18 ;N, 9.00.

EXAMPLE 40

[0513] Preparation of 5-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)- 1-(S)-phenylethyl]-N-methylamino}-N′-propyl-2-thiophenecarboxamide

[0514] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yt)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and 5-methylamino-NM-propyl-2-thiophenecarboxamide in 49% yield according to a procedure similar to that described in Example 1 (i).

[0515]¹H NMR (270MHz, CDCl₃) δ7.35-7.25 (5H, m), 7.18 (1H, d, J=4.4Hz), 5.33 (1H, d, J=4.9 Hz), 5.68-5 60 (1H, m), 4.86 (1H dd, J=7.0, 7.7Hz), 4.62 (1H, d, J=7.0 Hz), 4.5S (1H, d,-J=7.0Hz), 4.25-4.15 (1H, m), 3 40-3.30 (2H, m), 3.32 (3H, s), 3.13-3.00 (2H, m), 2.94 (1H, dd, J=6.2, 9 9Hz), 2.83 (3H, s), 2.80-2.70 (1H, m), 2.67-2.55 (2H, m), 2.15-2.00 (1H, m), 1.87-1.73 (IF, m), 1.70-1.50 (2H, m), 0.95 (3H, t, J=7.7Hz)

EXAMPLE 41

[0516] Preparation of 5-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl}-1-(S)-phenylethyl]-N-methylamino}-N′-propyl-2-thiophenecarboxamide

[0517] This was prepared from 5-{N-(2-(3-(S)methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamrino}-N′-propyl-2-thiophenecarboxarnide in 78% yield according to a procedure similar to that described in Example 2.

[0518]¹H NMR (270MHz, free amine, CDCl₃) δ7.38-7.24 (5H, m), 7.18 (1H, d, J=4.0 Hz). 5.84 (1H, d, J=4.4Hz), 5.70-5.60 (1H, m), 4.88 (1H, dd, J=6.0, 9.0Hz), 4.30-4.22 (1H, m), 3.40-3.30 (2H m), 3.15 (1H dd, J=9.2, 12.8Hz), 3.07-2.95 (2H, m), 2.81 (3H, s), 2.75 (1H. d, J=9.5Hz), 2.63 (1H, dd, J=4.8, 9.5Hz), 2.42-2.30 (1H, m), 2.22-2.05 (1H, m), 1.80-1.50 (4H m), 0.96 (3H, t, J=7.7Hz).

[0519] Fumaric acid salt: amorphous solid. IR(KBr): 3300, 1610cm⁻¹. MS m/z-388(M+H)⁺ Anal. Calcd for C₂₁H₂₉N₃O₂S·C₄H₄O₄·0.5H₂O·CH₄O: C, 57.34; H, 7.03; N, 7.71 Found C,57.37; H,7.31; N, 7.79

EXAMPLE 42

[0520] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino}-N′-propylbenzamide (i) Methyl 4-{N-[2-(3-(S)-methoxymethoxypyrroiidin-1-yl)-1-(S)-phenylethyl]amino}benzoate

[0521] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 4-aminobenzoate in 69% yield according to a procedure similar to that described in Example 1 (i).

[0522]¹H NMR (270MHz, CDCl₃) 8 7.75 (2H, d, J=8 8Hz), 7.37-7.27 (SH mn), 6.47 (2H, d, J=8.8Hz), 5.56 (1H, br. s), 4.65 (I K d, J=6.6Hz), 4.61 (1H, d, J=7.0Hz), 4.35-4.28 (1H,m), 4.26-4.23 (1H, m), 3.80 (3H, s), 3.36 (3H, s), 2.90-2.76 (3H. m), 2.62-2.51 (2H, m), 2.48-2.42 (1H, m), 2.18-2. 10 (1H, m), 1. 84-1 82 (1H, m)

[0523] (ii) 4- N-[2-(3 -( S)-Methox2methoxypyrrolidin- 1 -yl I -(S)-phenylethyl]amino]benzoic acid

[0524] This was prepared from methyl 4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino}benzoate in 100% yield according to a procedure similar to that described in Example 1 (ii).

[0525]¹H NMR (270MHz, CDCl₃) δ7.72 (2H, d, J=8 4Hz), 7.36-7.23 (5H, m), 6.42 (2H, d, J=8.4Hz), 5.80 (l, br. s), 4.694.65 (1H, m), 4.63 (H, d, J=7.0Hz), 4 60 (1H, d, J=7.0Hz), 4.394.37 (1H, m), 4.324.22 (lm), 3.34 (3H, s), 3.00-2.82 (3H, m), 2.66-2.48 (3H, m), 2.17-2.10 (1H, m), 1.95-1.78 (1H, m)

[0526] (iii) 4-{N-[2-(3-(S)-Methoxymethoxnpyrrolidin- -1)-1 -(S)-phenylethyl]amno}-N′-propylbenzamide

[0527] This was prepared from 4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino}benzoic acid and n-propylarine in 62% yield accordLng to a procedure similar to that described in Example 1 (iii).

[0528]¹H NMR (270MHz, CDCl₃) δ7.49 (2H, d, J=8.5Hz), 7.38-7.24 (5H, m), 6.48 (2H, d, J=8.8Hz), 5.95-5.80 (1H, m), 5.46 (1H, br. s), 4 65 (1H, d, J=7.0Hz), 4 61 (1H, d, J=7.0Hz), 4.32-4.23 (2H,m), 3.36 (3H, s), 3.38-3.31 (2H, m), 2.90-2.76 (3K m), 2.59 (1, dd, J=3.9, 10.8Hz), 2.53-2.42 (2K m), 2.18-2.11 (1K m), 1.83-1.82 (1H, m), 1.60-1.50 (2H, m), 0.93 (3H, t, J=7.3Hz).

EXAMPLE 43

[0529] Preparation of 4-{N-[2-(3-(S)-Hydroxylpyrrolidin-1-yl)-1-(S)-phenylethyl]amino }-N′-propylbenzamide

[0530] This was prepared from 4-{N-[2-(3-(S)-methoxyrnethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino}-N′-propylbenzamide in 67% yield according to a procedure similar to that described in Example 2.

[0531]¹H NMR (270MHZ, free amine, CDC1₃) 6 7.50 (2H. d. I=8.8Hz), 7.38-7.22 (5H, m), 6.48 (2H, d, J=8.8Hz), 5.95-5.80 (IV, m), 5.39 (1H, br. s), 4.39-4.29 (2H,m), 3.40-3.28 (2H, m), 2.99-2.84 (2H, m), 2.73-2.53 (3H,m), 2.40-2.31 (1H, m), 2.26-2.13 (1H, m), 1.90-1.67 (2H, m), 1.65-1.50 (2H, m), 0.94 (3H, t, J=7.3Hz). HCl salt:amorphous solid. 1R(KBr): 3350, 1610cm⁻¹. Anal. Calcd for C₂₂H₂₉N₃O₂·HCl·1.1H₂O:C 62.44; H, 8.05; N, 9.72 Found: C,62.36; 6,7.66 ; N. 9.92.

EXAMPLE 44

[0532] Preparation of 4-{N-[1-(S)-(3-Chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyyl-N-methylamino}-N′-propylbenzamide (i) Methyl 4{N-[1-(S)-(3-chlorophenyl}2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylimino}benzoate

[0533] This was prepared from the mixture of 2-(R)-(3-chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(S)-(3-chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and methyl 4-methylaminobenzoate in 66% yield according to a procedure similar to that described in Example 1 (i).

[0534]¹H NMR (270Ma, CDCl₃) o 7.90 (2H, d, I 8.8Hz), 7.30-7.14 (4H, m), 6.77 (2H, d, J=9.2Hz), 5.11 (1H, dd, J=7.0, 7.7Hz), 4.60 (1H, d, J=7.0Hz), 4.55 (1H, d, J=7.0Hz), 4.22-4.13 (1H-, m), 3.86 (3H, s), 3.30 (3H, s), 3.12-2.94 (2H, m), 2.90-2.78 (1H, m), 2.87 (311, s), 2.76-2.52 (3H1, m), 2.15-1.98 (1H, m), 1.85-1.70 (1H, m).

[0535] (ii) 4-JN-[14SI-(3-Chlorohenyl)-2-(3-(S)-metho=ethoxyvrrolidin-1-yl-ethyl]-N-methylamino]benzoic acid

[0536] This was prepared from methyl 4-{N-[1-(S)-3-chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino)benzoate in 96% yield according to a procedure similar to that described in Fxample 1 (ii).

[0537]¹H NMR(270MHz, CDCl₃) δ7.93 (2H, d, J=9.2Hz), 7.32-7.10 (4H, m), 6.82 (2H, d. J=9.2Hz), 5.40-5.25 (1H,m), 4.62 (1H, d, J=7.OHz), 4.58 (1H, d, J=7.0Hz), 4.30-4.18 (1H, m), 3.40-3.00 (3H, m), 3.31 (3H, s), 2.95-2.65(3H, m), 2.88 (3H, s), 2.20-2.00 (1H, m), 1.95-1.80 (1H, m).

[0538] (iii) 4-{N-[1-(S)-(3-Chlorophenyl)-2-(3-(S)-methoiymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide

[0539] This was prepared from 4-{N-[1-(S)-(3-chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylarnino}benzoic acid and propylamine in 77% yield according to a procedure similar to that described in Example 1 (iii).

[0540]¹H N-R (270MHz, CDCl₃) δ7.66(2EI d, I =9.2Hz), 7 30-7.13 (4H, m), 6 78 (2H, J=9.2Hz), 6.02-5.92 (1lH, m), 5.07 (1H. dd, J=6.6, 7.7Hz), 4.60 (1H, d, J=7.0Hz), 4.55 (1H, d, J=7.0Hz), 4.254.12 (1H, m), 3.45-3.35 (2H, m), 3.30 (3H, s), 3-12-2.93 (2H, m), 2.90-2.78 (1H, m), 2.85 (3H, s), 2.75-2.52 (3H, m), 2.13-1.97 (1H, m), 1.85-1.70 (1H, m), 1.69-1.54 (2H, m), 0.98(3H, t, J=7.3Hz).

EXAMPLE 45

[0541] Preparation of 4-{N-[1-(S)-(3-Chlorophenyl)-2-(3-(S)-hydroxpyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide

[0542] This was prepared from 4-{N-[1-(S)(3chlorophenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide in 83% yield according to a procedure sirilar to that described in Example 2.

[0543]¹H NMR (270MHz, free amine, CDCl₃) 6 7.67 (2H, d, J=9.2Hz), 7.30-7.14 (4H, m), 6.79 (21H, d, J=8.8Hz), 6.03-5.94 (1H, m), 5.09 (Il, dd, J=6.2, 8.8Hz), 4.27 4 18 (1H, m),₁ 3.45-3.35 (2H, m), 3.09 (1H, dd, J=8.8. 12.8Hz), 3.01 (1H, dd, J=6.2, 12.8Hz). 2.93-2.80 (1H, m), 2.84 (3H, s), 2.72 (1H, d, J=9.9Hz), 2.57 (K1, dd, J=5.0, 9.7Hz), 2.38-2.27 (1H, m), 2.11-2.02 (1K m), 1.80-1.55 (4H, m), 0.98 (3H, t, J=7.3Hz). Fumaric acid salt: amorphous solid. 1R(KBR) :3350, 1610cm⁻¹. MS m/z: 416(M+H)⁺

EXAMPLE 46

[0544] Preparation of 4-{N-[2-(3-(S)-Fluoropyrrolidin-1 -li)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide

[0545] (i) Methyi 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate

[0546] This was prepared from 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol and methyl methylaminobenzoate in 54% yield according to a procedure similar to that descnbed in Example 1 (i).

[0547]¹H NMR (270MHz, CDCl₃) δ7.89 (2H, d, J - 9.2Hz), 7.38-7.22 (5H, m), 6.78 (2H, d, J=9.2Hz), 5.25-4.95 (1H, m), 5.14 (1H, dd, J=6 6, 8.8Hz), 3.84 (3H, s), 3.18-3 00 (2S m), 2.95-2.75 (3H, m), 2.89 (3H, s), 2.60-2.50 (1H, m), 2.15-1.85 (2H, m).

[0548] (ii) 4-{N-[2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid

[0549] This was prepared from methyl 4-{N-[2-3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylarnino}benzoate in 100% yield according to a procedure similar to that described in Example 1 (ii).

[0550]¹H NMR (270MHz, CDCl₃) δ7.92 (2H, d, J=8.8Hz), 7.40-7.10 (5H, m), 6.83 (2H, d, l=8.8Hz), 5.40-5.00 (2H, m), 3.40-3.15 (2H, m), -3.10-2.70 (4H, m), 2.90 (3H, s), 2.30-1.90 (2H, m).

[0551] (iii) 4-{N-[2(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)phenylethyl]-N-methylamino}-N′-propylbenzamide

[0552] This was prepared from 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and n-propylamitie in 73% yield according to a procedure similar to that described in Example 1 (iii).

[0553]¹H NMR (270MHz, free amine, CDCl₃) δ7.65 (2K d, J=8.8Hz), 7.37-7.22 (5H, m), 6.79 (2H, d, J=8.8H7), 6.03-5.92 (1H, m), 5.25-4.95 (1H, m), 5.11 (I11, dd, J=6.2, 8.4Hz), 3.45-3.35 (2H, m), 3.18-3.02 (2H, m), 2.95-2.72 (3H, m), 2.87 (3H, s), 2.63-2.50 (1H, m), 2.18-1.85 (2H, m), 1.72-1.54 (2+, m), 0.97 (3H, t, J=7.3Hz) HCl salt:amorphous solid. 1R(KBr): 1605cm⁻¹. MS m/z 384(M+H)⁺Anal. Calcd for C₂₃H₃₀N₃OF·HCl·0.3H₂O·CH₄O C, 63.02; H, 7 84; N, 9.19 Found:C, 62.69; H, 8.17; N, 9.57.

EXAMPLE 47

[0554] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}-N′-propylbenzamide (i) Methyl 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-(R)-phenylethyl]-N-methylamino}benzoate

[0555] This was prepared from 2-(3{S)-methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidia-1-yl)-2-(S)-phenylethanol and methyl 4-methylaiinobenzoate in 49% yield according to a procedure similar to that described in Example 1 (i).

[0556]¹HN (270MHz, CDCl₃) δ7.88 (2H, d, J=8.8Hz), 7.34-7.23 (SH, m), 6.78 (2H, d, J=9.2Hz), 5.17 (I1, dd, J=7.0, 7.7Hz), 4.58 (1H, d, J=7.0Hz), 4.53 (1H, d, J=6.6Hz), 4.22-4.15 (1H, m), 3.85 (3R, s), 3.68-3.52 (I, m), 3.28 (3H, s), 3 08-3 04 (2H, m), 2.86 (3H, s), 2.76-2.67 (iH, m), 2.62-2.51 (2H ti), 2.08-1.97 (IK m), 1.83-1.72 (1H, m).

[0557] (ii) 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}benzoic acid

[0558] This was prepared from methyl 4-{N-[2-(3-(S)-methoxymethoxypyrrolidinr-1-yl)-1-(R)-phenylethyt]-N-methylamino}benzoate in 100% yield accordind to a procedure similar to that described in Example 1 (ii).

[0559]¹H NMR (270MHz, CDCl₃) δ7.89 (2H, d, J=9.2Hz), 7 33-7.18 (5H, m), 6.75 (2H, d, J=9.2Hz), 5.15 (1H, dd, J=7.0, 7.3Hz), 4.57 (IR, d, J=7.0Hz), 4.52 (1H, d, J=7.0Hz), 4.25-4.15 (1H, m), 3 33 (3H. s), 3 05 (1H, d, l=6.6Hz), 2.88-2.84 (1H, m). 2.85(3H, s), 2.76-2.62 (IR, m), 2.50-2.61 (3H, m), 2.07-2.02 (1H, m), 1.78-1.73 (1H, m).

[0560] (iii) 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethyl]-N′-methylamino}-N′-propylbenzamide

[0561] This was prepared from 4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}benzoic acid and n-propylamine in 60% yield according to a procedure similar to that described in Example 1 (iii).

[0562]¹H NMR (270MHz, CDCl₃) δ7.63 (2H, d, J=9.2Hz), 7.34-7.24 (5H, m), 6 79 (2H, d, J=9.2Hz), 5.98-5.82 (1H m), 5.13 (1H,.t, J=7.3Hz), 4.58 (1H, d, J=6.6Hz), 4.54 (1H, d, J=7.0Hz), 4.264.13 (lHm), 3.43-3.34 (2H, m), 3.29 (3H, s), 3.06 (2H, d, J=7.3Hz), 2.91-2.88 (1H, m), 2.85 (3H, s), 2.73-2.67 (1H, m), 2.61-2.54 (2H, m) 2.11-1.98 (1H, m), 1.84-1.72 (1H, m), 1.65-1.57 (2H, m), 0.97 (3H, t, J=7.3Hz).

EXAMPLE 48

[0563] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(R)-phenylethyl[-N-methylamino]-N′-propylbenzamide

[0564] This was prepared from 4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}-N′-propylbenzamide in 15% yield according to a procedure similar to that described in Example 2.

[0565]¹H NMR (270Mz free amine, CDCl₃) δ7.59 (2H, d, J=9.2Hz), 7.28-7.16 (5H, m), 6.75 (21H, d, J=8.8Hz), 6.07-5.94 (1H, m), 5.12 (1H, t, J=7.3Hz), 4.184.13 (1H, m), 3.35-3.27 (2I-, m), 3.03 (2H, d, J=7.8Hz), 2.92-2.86 (1H, m), 2.73 (3H, s), 2.66 (1H, d, J=9.9Hz), 2.50 (1H, dd, J=4.8, 9.7Hz), 2.38-2.33 (1H, m), 2.09-1.96 (2H, m), 1.67-1.46 (3Ii, m), 0.90 (3H, t, J=7.3Hz) IR(neat): 3350, 1610cm⁻¹. HCl salt:amorphous solid. Anal. Calcd for C₂₃H₃₁N₃O₂·HCl·1.9H₂O:C, 61.52; H, 8.37; N, 9.20. Found: C, 61.33; H, 7.97; N, 9.33.

EXAMPLE 49

[0566] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-pyrrolidinebenzamide

[0567] This was prepared from 4-(N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and pyrrolidine in 77% yield according to a procedure similar to that described in Example 1 (iii).

[0568]¹H NM (270hl CDCl,) 8 7 47 (2H, d, J=8.8Hz), 7.33-7.21 (SH, m), 6 77 (2H, d, J=8.8Hz), 5.11 (1H, dd, J=6.6, 7 3Hz), 4 60 (1H, d, J=7.0Hz), 4 56 (1H, dd, J=7.0Hz), 4.21-4.15 (1H, m), 3.62-3.52 (4H, m), 3 30 (3H, s), 3.12-2.97 (2H, m), 2.82 (3H, s), 2.75-2.54 (4H, m), 2.09-1.74 (6H, m)

EXAMPLE 50

[0569] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidn-1-yl)-1-(S)-phenylethyl]-N-methylamino}-pyrrolidinebenzamide

[0570] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethylJ-N-methylamino}-pyrrolidinebenzaide in 51% yield according to a procedure sinilar to that described in Example 2.

[0571]¹H NMR (270MHz, free amine, CDCl₃) δ7.49 (2H, d, J=9.2Hz), 7.46-7 23 (5H, m 6.79 (2H, d, J=8.8Hz), 5.14 (1H, dd, J=6.2, 8.8Hz), 4.24-4.20 (1H, m), 3.68-3.52 (4H, m), 3.12 (1H, dd, J=8.8, 12.6Hz), 3.03 (1H, dd, J=6.2, 12.8Hz), 2.95-2.87 (1H, m), 2.81 (3H, s), 2.75 (1H, d, J=10.3Hz), 2.55 (1H, dd, J=4.8, 9.5Hz), 2.35-2.27 (1H, m), 2.17-2.03 (1H, m), 1.98-1.82 (6H, m) IR(nea;): 3400, 1610cm⁻¹. HCl salt:amorphous solid. Anal. Calcd for C₂₄H₃₁N₃O₂·HCl·2H₂O: C, 61.65; H, 8.08; N, 8.83 Found: C,61.86; H, 7.79; N,9.02.

EXAMPLE 51

[0572] Preparation of 4-{N-[2-(3-(S)-tert-Butyldimethylsilyloxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-ethoxybenzamide (i) Methyl 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate

[0573] This was prepared from methyl 4-{N-(2-(3-(S)-methoxymethoxypyrroidn-1-yl)-1-(S)-phenylethyl]-N-methylaminoybenzoate in 100% yield according to the procedures similar to those described in Example 2.

[0574]¹H NMR (270z, CDCl₃) δ7.90(2H, d, J=9 2Hz), 7 36-7.23(5H, m), 6 80(2H, d, J=9 2Hz), 5 18(1H, dd, J=5.9, 9 OHz), 4 244 20(1H, m), 3 85(3H, s), 3 13(1H, dd, J=5.9, 12.8Hz), 2.94-2.88(2H, m), 2.85(3H, s), 2.73(1H, d, J=9.9Hz), 2.56(1H, dd, J=4.8, 9.5Hz), 2.36-2 30(1H, m), 2 27-2 05(1H, m), 1.80-1.50(2H,m)

[0575] (ii) Methyl 4-{N-[2-(3-(S)-tert-butyldimethylsilyloxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate

[0576] To a stirred solution of methyl 4-{N-[2-3-(S)-hydroxypyrrolidin-1-yl)-(S)-phenylethyv]-N-methylarnino)benzoate (865 mg, 2 44 mmol) in DMF (10 ml) was imidazole(1.54 g, 24.4 mmol) and tert-butyldimethylsilylchloride(1.83 g, 12.2 mmol) at 0° C. After 3 hr stirring, saturated NaHCO₃ aqueous solution was added to the reaction mixture and extracted with CH₂CI₂. The extract was washed uith water and brine, dried(Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 40 g, CH₂C₂/MeOtH: 100/1-50/1) to give 760 mg(66%) of title compound.

[0577]¹H NMR (270MHz, CDCl₃) δ7.79(2H, d, J=9.2Hz), 7.24-7.14(5H, m), 6.68(2H, d, J=9.2Hz), 5.05(1H, dd, J=6.2, 7.3Hz), 4.214.12(1H, m), 3.75(3H, s), 2.97-2.92(2H, m), 2.82-2.76(1H, m), 2.75(3H, s), 2.58-2.53(2H, m), 2.27(1H, dd, J=4.4, 9.2Hz), 1.93-1.86(1H, m), 1.58-1.47(1H, m), 0.74(9H, s), 0.01(6H, s).

[0578] (iii) 4-{N-[2-(3-(S)-tert-Butylidimethylsilyloxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino}benzoic acid

[0579] This was prepared from methyl 4-{N-[2-(3-(S)-tert-butyldimethylsilyloxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}bernzoate in 32% yield according to the procedures similar to those described in Example 1-(ii)

[0580]¹H NM (270MHz, CDCl₃) δ7.90(2H, d, J=9.2Hz), 7 32-7.23(5H, m), 6.80(2H, d, J=9.2Hz), 5.29-5 26(1H,m), 4 324 25(1H, m), 3.26-3.12(2H, m), 3,12-3 06(1H, m) 2.85(3H, s), 2.73-2.65(2H, m), 2.46-2.41 (1H, m,), 2.07-2.00(1H, m), 1.71-1.62(1 H, m, 0.84(91, s), 0.01(6H, s).

[0581] (iv) 4-{N-[2-(3-(S)-tert-Butyldimethylsilyloxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino}-N′-ethoxybenzamide

[0582] This was prepared from 4-{N-[2-(3-(S)tert-butyldimethylsilyloxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamiino}benzoic acid and O-ethylhydroxyl amine in 41% yield according to the procedures similar to those described in Example 1-(iii)

[0583]¹H NMR (270MHz, CDCl₃) δ8.39(1H, br.s), 7.62(2H, d, J=8.8Hz), 7.34-7.24(5H, m), 6.78(2H, d, J=9.2Hz), 5.11-5.09(1H, m), 4.32-4.23(1H, m), 4.07(2H, q, J=7.0Hz), 3.06-3.02(1H, m), 2.92-2.86(1H, m), 2.84(3H, s), 2.68-2.63(2Hz m), 2.38(1H, dd, J=4.4, 9.2Hz), 2.03-1.96(1H, m), 1.68-1.62(2H, m), 1.32(3H, t, J=7 OHz), 0 84(9H, s), 0.01(6H, s).

EXAMPLE 52

[0584] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-ethoxbenzamide

[0585] To a stirred solution of 4-{N-[2-(3-(S)-tert-butyldimethylsilyloxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino} -N′-ethoxybenzamide (44.7 mg, 0.090 mmol) in THF(1 ml) was added 1.0 M solution of tetrabutylammonium fluoride in THF(0.273 ml, 0.273 mmol) at room temperature. After 18 hr stirring, saturated NaHCO₃ aqueous solution was added to the reaction mixture and extracted with CH₂Cl₂. The extract was washed with water and brine, dried(Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel, 20 g, CH₂Cl₂/MeOH. 25/1-10/1) to give 28.4 mg(82%) of title compound.

[0586]¹H NMR (270MHz, free amine, CDCl₃) δ8.60(1H, br.s), 7 64(2H, d, J=9.2Hz), 7.36-7.24(5HL m), 6.80(21L d, J=9.2Hz), 5.16(1H~dd, J=5.9, 9.2Hz), 4.24-4.20(1H, m). 4.06(2H, q, J=7.0Hz), 3.14(1HK dd, J=9 2, 13.2Hz), 3.04(1H, dd, J=5.9, 12.0Hz),2.89-2.83(1H, m), 2.83(3H, s), 2.76(1H, d, J=9.5Hz), 2.57(1H, dd, J=4 8, 9.9Hz), 2.38-2.29(1H, m), 2.16-2.03(1HL m), 1.90-1.56(2H, m), 1.32(3HL t, J=7.0Hz).

[0587] HCl salt:amorphous solid. Anal. Calcd for C₂₂H₂₉N₃O₃·HCl·0.7H₂O C,58.04, H, 8.00, N,8.46 Found:C,58.26; H, 8.40; N,8.58.

EXAMPLE 53

[0588] Preparation of 4-{N-[2-3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyl]amino} -morpholinebenzamide

[0589] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylarnino~benzoic acid and morpholine in 54% yield according to the procedures similar to those described in Example 1 (iii).

[0590]¹H NMR (270MHz, CDCl₃) δ7.32(2H, d, J=8.8Hz), 7.29-7.28(5H, m), 6.78(2H, d, J=8.8Hz), 5.10(1H, dd, J=7.0, 7.7Hz), 4.60(1H, d, J=7.0Hz), 4.55(1H, d, J=6.6Hz), 4.22-4.13(1H, m), 3.68-3.67(8H, m), 3.30(3H, s), 3.07-3.02(2H, m), 2.90-2.80(1H, m), 2.84(3H, s), 2.75-2.57(3H, m), 2.07-2.02(1H, m), 1.81-1.72(1H, m)

EXAMPLE 54

[0591] Preparation of 4{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-(S)-phenylethyl]-N-methylamino}-morpholinebenzamide

[0592] This was prepared from 4-{N-[2-(3-(S)-rnethoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamnino}-morpholinebenzamide in 76% yield according to the procedures similar to those described in Example 2.

[0593]¹H NMR (270MHz, free amine, CDCl₃) δ7.34(2H, d, J=9.2Hz), 7.30-7.24(5H, m), 6.80(2H, d, J=8.8Hz), 5.13(1H, dd, J=6.6, 8.8Hz), 4.274.21(1H, m), 3.81-3.58(8H, m), 3.16-2.96(2H, m), 2.92-2.87(1H, m), 2.82(3H, s), 2.75(I, d, J=9 2Hz), 2.53(1H dd, J=4.4, 9.5Hz), 2.36-2.27(1H, m), 2.12-2.09(1H, m), 1.75-1.60(2H, m)

[0594] IR(neat): 3400, 1610cm⁻¹.

[0595] HCl salt:amorphous solid. MS m/z:410(M+H)⁺

EXAMPLE 55

[0596] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1 -yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(3-hydroxypropyl)benzamide

[0597] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and 3-amino-1-propanol in 48% yield according to the procedures similar to those described in Example 1 (iii)

[0598]¹H NMR (270MHz, CDCl₃) δ7.66(2H, d, J=9.2Hz) 7.40-7.20(5H, m), 6.30(2H, d, J=8.8Hz), 6.40-6.30(1H, m), 5.14(1H, dd, J=7.0, 7.7Hz), 4 60(1H, d, J=6.6Hz). 4.55(1H, d, J=6.6Hz), 4.25-4.13(1H, m), 3.73-3.55(4H, m), 3.30(3H, s), 3.13-3.00(2H, m), 2.90-2.80(1H, m), 2.86(3H, s), 2.78-2.52(3H, m), 2.13-1 98(1H, m), 1.81-1.45(4H, m)

EXAMPLE 56

[0599] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(3-hydroxypropyl)benzamide

[0600] This was prepared from 4-{N-[2-(3-(S)-methoxyrmethoxypyrrolidin-1-yl)-1-(S)phenylethyl]-N-methylarnino}-N′-(3-hydroxypropyl)benzamnide in 82% yield according to the procedures similar to those described in Example 2.

[0601]¹H NMR (270MHz, free amine, CDCl₃) δ7.66(2H, d, J=9.2Hz), 7.35-7.26(5H, m), 6.81(2H, d, J=9.2Hz), 6.42-6.33(1H, m), 5.15(Ih, dd, J=5.9, 8.8H7), 4.27-4.17(1H, m), 3.66(2H, t, J=5.5Hz), 3.59(2H, t, J=5.9Hz), 3.l3(1H, dd, J=9.2, 12.8Hz), 3.03(1H, dd, J=5.9, 12.8Hz), 2.94-2.86(1H, m), 2.84(3H, s), 2.72(1H, d, J=9.5Hz), 2.56(1H, dd, J=4.8, 9.9Hz), 2.36-2.28(1H, m), 2.13-2.03(1H, m), 1.79-1.61(5H, m)

[0602] IR(neat): 3350, 1610cm⁻¹.

[0603] HCl salt:amorphous solid. MS m/z:398(M+H)⁺

EXAMPLE 57

[0604] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(R)-hydroxypropyl)benzamide

[0605] This was prepared from 4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and (R)-(−)-1-amino-2-propanol in 83% yield according to the procedures similar to those described in Example 1 (iii)

[0606]¹H NMR (270MHz, CDCl₃) δ7.67(2H, d, J=8 8Hz), 7 40-7 20(5H, m), 6 80(2H, d, J=8.8Hz), 6.50-6.40(1H, m), 5.14(1H, dd, J=7 0, 7 7Hz), 4.59(1H, d, J=7.0Hz), 4.55(1H, d, J=7 0Hz), 4.23-4 13(1H, m), 4 07-3 95(1H. m), 3 66-3 55(1H, m), 3.40-3.20(1H, m), 3.30(3H, s), 3 13-3 00(2H, m), 2.90-2.80(1H, m), 2.85(3H. s), 2.76-2.52(3H, m), 2.13-1.98(1HK m), 1.85-1.45(2H, m), 1.23(3H, d, J=6.2Hz).

EXAMPLE 58

[0607] Preparation of 4-{-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(R)-hydroxypropyl)benzamide

[0608] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylarnino}-N′-(2-(R)-hydroxypropyl)benzarnide in 84% yield according to the procedures sisnilar to those described In Example 2.

[0609]¹H NMR (270Mz, free amine, CDCl₃) δ7.68(2H, d, J=8.8Hz), 7 40-7 20(5H, m), 6.82(2H, d, J=8.8Hz), 6.50-6.38(1H, m), 5.16(1H, dd, J=5.9, 8.8Hz), 4.28-4.18(1H, m), 4.10-3 95(1H, m), 3.66-3.55(1H, m), 3.40-3 35(1H, m), 3 16-3 00(2H, m), 2.95-2.80(1H, m), 2.84(3H, s), 2.74(1H, d, J=9.2Hz), 2.56(1H, dd, J=4.4, 9.5Hz), 2.40-2.25(1H, m), 2.17-2.00(1H, m), 1.90-1 40(3H, m), I 24(3H, d, J=6.6Hz)

[0610] IR(neat) 3350, 1610cm⁻¹

[0611] HCl salt: amorphous solid. MS m/z:398(M+H)⁺

[0612] Anal. Calcd for C₂₃H₃₁N₃O₃·HCl·0.85CH₃O C, 62.11, H, 7.74, N, 9.11 Found: C,62.50; H, 8.13; N,9 37.

EXAMPLE 59

[0613] Preparation of 4-{N-[2-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylenyl]-N-methylamino)-N′-isobutylbenzamide

[0614] This was prepared from 4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)benzoic acid and isobutylamine in 72% yield according to the procedures similar to those described in Example 1 (iii).

[0615]¹H NMR (270MHz, CDCl₃) δ7.65(2H, d, J=8.8Hz), 7.34-7 24(5H, m), 6.80(2H, d, J=8.8Hz), 6 04-5.92(1H, m), 5.18-5 08(1H, m), 4 59(1H, d, J=7.0Hz), 4.55(1H, d, J=6.6Hz), 4.22-4.13(1H, m), 3.29(3H, s), 3.28-3.23(2H, m), 3. 10-3.02(2H, m), 2.84-2.80(1H, m), 2.84(3H, s), 2.72-2.57(3H, m), 2.12-1.98(1H, m), 1.89-1.79(1H, m), 1.78-1.69(1H, m), 0.96(6H, d, J=6.6Hz).

EXAMPLE 60

[0616] Preparation of 4-{N-[2-(3-(S)Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-isobutylbenzamide

[0617] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypylrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-isobutylbenzamide in 86% yield according to the procedures similar to those described in Example 2.

[0618]¹H NMR (270MHz, fee amine, CDCl₃) δ7.66(2H, d, J=8.8Hz), 7.35-7.26(5H, m), 6.81(2H, d, J=8 g8Hz), 6.06-5.96(1H, m), 5.15(1H, dd, J=5.9, 8.8Hz), 4.26-4.18(1H, m), 3.26(2H, t, J=6.2Hz), 3.13(1H, dd, l=8.8, 12.8Hz), 3.03(1H, dd, J=5.9, 12.8.Hz), 2.92-2.85(1H, m), 2.84(3H, s), 2.73(1H, d, J=9.5H), 2.56(1H, dd, J=4.6, 9 7Hz), 2.36-2.28(1H, m), 2.16-2.04(1H, m), 1.96-1.58(3H, m), 0.97(6H, d, J=7.0Hz).

[0619] IR(neat): 3350, 1610cm⁻¹.

[0620] HCl salt:amorphous solid. MS m/z:396(M+H)⁺

[0621] Anal. Calcd for C₂₄H₃₃N₃O₂·HCl·0.5H₂O C, 65.36 H. 8.00; N, 9.53 Found: C,65.58 ; H, 8.17 N,9.48.

EXAMPLE 61

[0622] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-allylbenzamide

[0623] This was prepared from 4-(N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and allylamine in 33% yield according to the procedures similar to those described in Example 1 (iii).

[0624]¹H NMR (270MHz, CDCl₃) δ7.67(2H, d, I=8.8Hz), 7.31-7.26(5H, m), 6 79(2H, d, J=9.2Hz), 6.01-5.88(2H, m), 5.28-5.27(1H, m), 5.21-5.1 1(2H, m), -4 59(1H, d, J=7.0Hz), 4.55(1H, d, J=6.6Hz), 4.25-4.13(1H, m), 4.094.04(2H, m), 3.29(3H, s), 3.07-3.03(2H, m), 2.85-2.80(1H, m), 2.85(3H, s), 2.75-2.67(1H, m), 2.64-2.56(1H,m), 2.06-2.01(1H, m), 1.76-1.60(1H, m), 1.60-1.52(1H, m).

EXAMPLE 62

[0625] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl-N-methylamino}-N′-allylbenzamide

[0626] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)-N′-allylbenzamide in 52% yield according to the procedures similar to those described in Example 2.

[0627]¹H NMR (270MHz, free amine, CDCl₃) δ7.68(2H, d, J=8.8Hz), 7.35-7 26(5H, m), 6.81(2H, d, J=8.8Hz), 6.01-5.89(2H, m), 5.28-5.12(3H, m), 4.274.19(1H, m), 4.09-4.05(2H, m), 3.13(1H, dd, J=9.2, 12.8Hz), 3.03(1H, dd, J=5.9, 12.8Hz), 2.92-2.86(1H, m), 2.84(3H, s), 2.73(1H, d, I=9.2Hz), 2.56(1H, dd, l=4.8, 9.5Hz), 2.33-2.30(1H,m), 2.27-2.08(1H, m), 1.67-1.48(2H, m).

[0628] IR(neat): 3350, 1610cm⁻¹.

[0629] HCl salt:amorphous solid. MS m/z:380(M+H)⁺

[0630] Anal. Calcd for C₂₃H₂₉N₃O₂·Hcl·0.1H₂O·CHO: C, 64.09 H, 7.66 N, 9.34 Found: C,63.86; H, 7.85; N,9.32.

EXAMPLE 63

[0631] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin- 1-vt)- l -(S)-phenylethyl]-N-methylamino}-N′-cyclopropylbenzamide

[0632] This was prepared fiom 4-{(N-[2-(3-(S)methoxymethoxypyrrolidin-1-yl)-1(S)-phenylethyl]-N-methylamino}benzoic acid and cyclopropylamine in 48% yield according to the procedures similar to those described in Example 1 (iii).

[0633]¹H NMR (270MHz, CDCl₃) δ7.61(2H, d, J=8.8Hz), 7 33-7.22(5FL m), 6 78(2H, d, J=8.8Hz), 6.11-6.02(1H, m), 5.15-5.11(1H, m), 4.59(1H, d, J=6.6Hz), 4 55(1H, d, J=6.6Hz), 4.19-4.14(1H, m), 3.29(3H, s), 3.07-3.03(2H, m), 2.90-2 80(1H, m), 2.84(3H, s), 2.72-2.66(1H, m), 2.64-2.56(2H,m), 2.08-2.01(1H, m), 1.79-1.73(1H, m), 1.37-1.25(1H, m), 0.94-0.80(2H, m), 0 60-0 54(2H, m).

EXAMPLE 64

[0634] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-cyclopropylbenzamide

[0635] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxy~yrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-cyclopropylbenzaraide in 76% yield according to the procedures similar to those described in Example 2.

[0636]¹H NMR (270Mlz, free amine, CDCl₃) δ7.63(21, d, J=9.2Hz), 7.35-7.23(5H, m), 6.79(2H, d, J=8.8Hz), 6.12-6.04(1H, m), 5.15(1lK, aa, J=).9, 8.8Hz), 4.24-4.19(1H, m), 3.13(1H, dd, l=9.2, 12.8Hz),. 3.03(1H, dd, J=5.9, 10.3Hz), 2.94 2.84(2H, m), 2.83(3H, s), 2.78(1H, d, J=9.5Hz), 2.58-2.53(1H,m), 2.33-2.31(1H m), 2.11-2.08 (1H, m), 1.68-1.61(2K m), 0.87-0.80(2H, m), 0 60-0 54(2H, m).

[0637] IR(neat): 3350, 1610cm⁻¹.

[0638] HCl salt:amorphous solid. MS m/z:380(M+H)⁺

[0639] Anal. Calcd for C₂₃H₂₉N₃O₂·HCl·0.8H₂O C, 64.19 H, 7.40, N, 9.76 Found. C,64.04 H, 7.50 ,N,9.83

EXAMPLE 65

[0640] Preparation of 4-N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-]-(S)-phenlethyl]-N-methylamino}-N′-(S)-sec-butylbenzamide

[0641] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaminolbenzoic acid and (S)-sec-butylamine in 18% yield according to the procedures similar to those described in Example 1 (iii)

[0642]¹H NMR (270MHz, CDCl₃) δ7.65(2H, d, J=8 8Hz), 7.40-7.20(5H, m), 6.79(2H, d, J=8.8Hz), 5.74(1H, d, J=8.4Hz), 5.13(IFL dd, J=6.6, 8.1Hz), 4.59(1H, d, J=7.0Hz), 4.55(1H, d, J=7.0Hz), 4.25-4 05(2H, m), 3 30(3H, s), 3 15-2 95(2H, m), 2.90-2.80(1H m), 2.85(3H, s), 2.76-2.55(3H, m), 2.13-l.98(1I, m), 185-1.70(1H, m), 1.65-1.50(2H m), 1.20(3H, d, J=6.6Hz), 0.95(3H t, J=7.7Hz).

EXAMPLE 66

[0643] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(S)-sec-butylbenzamide

[0644] This was prepared from 4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(S)-sec-butylbenzamide in 100% yield according to the procedures similar to those described in Example 2.

[0645]¹H NMR (270QHz, free amine, CDCl₃) δ7.65(2H d, J=9.2Hz), 7.40-7.20(5H, m), 6.80(2H, d, J=9.2Hz), 5.76(1H, d, J=8 4Hz), 5 14(1H, dd, J=6.2, 8.8Hz), 4.25-4.05(2H, m), 3.17-2.98(2H, m), 2.95-2.78(1H, m), 2.83(3H, s), 2.72(1H, d, J=9.5Hz), 2 57(1H, dd, J=4.8, 9.5Hz), 2.40-2.28(1H, m), 2.20-1.95(2H, m), 1.70-1.50(3K, m), l.20(3H, d, J=6,6Hz), 0.95(3H, t, J=7.3Hz)

[0646] HCl salt:amorphous solid. MS m/z:396(M+H)⁺

[0647] Anal. Calcd for C₂₄H₃₃N₃O₂·HCl·0.3H₂O·CH₄O, C, 63.96 H, 8.29; N, 8.95 Found C,64.14; H, 8.01 N,8.70

EXAMPLE 67

[0648] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenyl]-N-methylamino}-N′-(R)-sec-butylbenzamide

[0649] This was prepared from 4-{ N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino benzoic acid and (R)-sec-butylamine in 18% yield according to the procedures similar to those described in Example 1 (iii).

[0650]¹H NMR (270MHZ, CDCl₃) 6 7.65(2H, d, I=8.8Hz), 7.33-7.23(5H, m), 6.79(2H, d, J=9.2Hz), 5.74(1H, d, J=8.1Hz), 5.13(1H, dd, J=6.6, 7.7Hz), 4.59(1H, d, I=6.6Hz), 4.55(1H, d, J=6.6Hz), 4.19-4.08(2H, m), 3.29(3X s), 3.09-2.98(2H, m), 2.90-2.80(1H, m), 2.84(3H, s), 2.72-2.57(3H, m), 2.13-1.98(1H, m), 1.78-1.75(1H, m), 1.60-1.49(2H, m), 1.20(3H, d, J=6.6Hz), 0.94(3H, t, J=7.7Hz).

EXAMPLE 68

[0651] Preparation of 4-N-{2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′- (R)-sec-butylbenzamide

[0652] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypypolidin-1-yl)-1-(S)-phenylethyl]-N-methylanino)-N′-R)-sec-butylbenzamide in 95% yield according to the procedures similar to those described in Example 2.

[0653]¹H NMR (270MHz, free amine, CDCl₃) δ7.65(2H, d, J=8.8Hz), 7.40-7 20(5H, m), 6.80(2H, d, J=8S8Hz), 5.78(1H, d, J=8.3Hz), 5.14(1H, dd, J=5.9, 8.8Hz), 4.25-4.03(2H, m), 3.17-2.98(2H, m), 2.95-2.78(1H, m), 2.83(3H s), 2.71(1H. d, J=9 5Hz). 2.58(1H, dd, J=4.8, 9.5Hz), 2.42-2.30(1H, m), 2.23(1H, br.s), 2.15-2.00(1H, m), 1.70-1.50(3H, m), 1.20(3H, d, J=6.6Hz), 0.95(3H, t, J=7.3Hz).

[0654] HCl salt:amorphous solid. MS m/z:396(M+H)⁺

[0655] Anal. Calcd for C₂₄H₃₃N₃O₂·HCl·0.4H₂O·CH₄O:C, 63.72; H, 8.30; N, 8.92 Found C,63.96; H, 8.08; N,9.08.

EXAMPLE 69

[0656] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenyiethyl]-N-methylamino}-N′-propargylbenzamide

[0657] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino~benzoic acid and propargylamine in 18% yield according to the procedures similar to those described in Example 1 (iii).

[0658]¹H NMR (270MHz, CDCl₃) δ 7.65(2H, d, J=8.8Hz), 7 34-7 24(5H, m), .6 80(2H, d, J=9.2Hz), 6.12-6.03(1H, m), 5.14(1H, dd, J=6.6, 73Hz), 4.59(1H, d, J=7.0Hz), 4.55(1H, d, J=7.OHz), 4.23(2H, q, J=2.6Hz), 4.19-4.14(1H. m), 3.29(3H, s), 3.07-3.03(2H, m), 2.85-2.80(1H, m), 2.85(3H, s), 2.75-2.70(1H, m), 2.67-2.56(2H, m), 2.25(1H, t, J=2.6Hz), 2.08-2.01(1H, m), 1.87-1.70(1H, m).

EXAMPLE 70

[0659] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrroidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-prolpargylbenzamide

[0660] This was prepared from 4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propargylbenzamide in 77% yield according to the procedures similar to those described in Examplee 2.

[0661]¹H NMR (270MHz, free amine, CDCl₃) δ7.67(2H, d, J=8.8Hz), 7.35-7:24(5H, m), 6.81(2H, d, J=8.8Hz), 6.13-6.03(1H, m), 5.16(1H, dd, J=5.9, 9.0Hz), 4.24-4.21(3H, m), 3.13(1H, dd, J=9.5, 12.8Hz), 3.03(1H, dd, J=5 9, 12.8Hz), 2.93-2-86(1H, m), 2.84(3H, s), 2.73(1H, d, J=8.3Hz), 2.58-2.53(1H, m), 2.32-2.24(2H, m), 2 11-2 O5(1H, m), 1.76-1.58(2H, m).

[0662] IR(neat): 3300, 1610cm⁻¹.

[0663] HCl salt:amorphous solid. MS m/z:378(M+H)⁺

[0664] Anal. Calcd for C₂₂H₂₇N₃O₂·HCl·0.8H₂O·CH₄O C, 62.61; H, 7.36, N, 9.13 Found 62.23, H, 7.26; 9.50.

EXAMPLE 71

[0665] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(3,3,3-trifluoropropyl)benzamide

[0666] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoic acid and 3,3,3,-trifluoropropylamine in 39% yield according to the procedures similar to those described in Example 1 (iii)

[0667]¹H NMR (270MHz, CDCl₃) δ7.63(2H, d, J=8 8Hz), 7.3 1-7 24(5H, m), 6 80(2H, d, J=9.2Hz), 6.21-6.12 (1H, m), 5.14(1H, dd, J=7.0, 81Hz), 4.59(1H, d, J=7.0Hz), 4.55(1H, d, J=7.0Hz), 4.214.12(1H, m), 3.69(2H, q, J=6.2Hz), 3.29(3H, s), 3.07-3.03(2H, m), 2.85(3H, s), 2.84-2 80(1H, m), 2 72-2.67(1H, m), 2.64-2.56(2H, m), 2.50-2.38(2H, m), 2.08-2.01(1H, m), 1.77-1.76(1H, m).

EXAMPLE 72

[0668] Preparation of 4-{N-[2-3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(3,3,3,-trifluoropropyl)benzamide

[0669] This was prepared from 4-(N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(3,3,3,-trifluoropropyl)benzamnide in 69% yield according to the procedures similar to those described in Example 2.

[0670]¹H NMR (270MMH, fiee amine, CDC1₃) 6 7.6)(2fl, d, J=8 8Hz), 7.36-7 26(5H, m), 6.81(2H, d, J=9.2Hz), 6.26-6.20 (1H, m), 5.16(1H, dd, J=5 9, 9.2Hz), 4.25-4.19(1H, m), 3.69(2H, q, J=6.2Hz), 3.17-3 02(2H, m), 299-2 88(1H, m), 2.84(3H, s), 2.80-2.72(1H, m), 2.59-2.53(1H, m), 2.52-2.38(2H, m), 2.37-2.28(1H, m), 2.16-2.05(1H, m), 1.80-1.75(2H, m).

[0671] IR(neat): 3350, 1610cm⁻¹.

[0672] HCl salt:amorphous solid. MS m/z:436(M+H)⁺

[0673] Anal Calcd for C₂₃H₂₈N₃O₂F₃·HCl·0.4H₂O C, 57.65, H, 6.27, N, 8.77 Found C,57.60, H, 6.26, N,8.50

EXAMPLE 73

[0674] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxyovrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxyoropyl)benzamide

[0675] This was prepared from 4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino benzoic acid and (S)-(−)-1-amino-2-propano n 55% yield according to the procedures similar to those described in Example 1 (iii).

[0676]¹H NMR (270MHZ, CDCl₃) δ7.67(2H, d, J=9.2Hz), 7 40-7 20(5H, m), 6 80(2H, d, J=8.8Hz), 6.50-6.40(1H, m), 5.14(1H, dd, J=7.0, 7.7Hz), 4.60(1H, d, J=6.6Hz), 4 55(1H, d, J=7.0Hz), 4.23-4.13(1K m), 4 07-3 95(1H, m), 3 66-3 55(1H, m), 3.42-3.25(1H, m), 3.30(3K, s), 3.13-3.00(2H, m), 2.90-2.80(1H, m), 2.86(3H, s), 2.76-2.52(3H, m), 2.13-1.98(1H, m), 1.85-1.45(2H, m), 1.23(3H, d, J=6.2Hz).

EXAMPLE 74

[0677] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamide

[0678] This was prepared from 4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamide in 81% yield according to thie procedures similar to those described in Example 2.

[0679]¹H NMR (270MHz, free amine, CDCl₃) δ7.68(2H, d, J=8.8Hz), 7.40-7.20(5H, m), 6.80(2H, d, J=8.8Hz), 6.60-6.50(1H, m), 5 15(1H, dd, J=5 9, 9.2Hz), 4 284 18(1H, m), 4.07-3.93(1H, m), 3.66-3.55(1H, m), 3 35-3.23(1H. m), 3.13(1H, dd, J=9.2, 12.8Hz), 3.03(1H, dd, J=5.9, 12.8Hz), 2.95-2.80(1H, m), 2.83(3H. s), 2.72(1H, d, J=9.5Hz), 2.56(1H, dd, J=4.8, 9.9Hz), 2.40-2.25(1H, m), 2.20-1.75(3H, m), 1 70-1 55(1H, m), 1.22(3K d, J=6.2Hz).

[0680] IR(neat) 3350, 1610cm⁻¹.

[0681] Maleic acid salt:amorphous solid MS m/z:396(M−H)

[0682] Anal. Calcd for C₂₃H₃₁N₃O₃·C₄H₄O₄·0.3H₂O: C, 62.49; H, 6.91; N, 8.10 Found: C,62.65; H, 7.24; N,7.90.

EXAMPLE 75

[0683] Preparation of 4-{N-[1-(R)-(3-Methoxymethoxyphenyl)-2-(3-S-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide (i) Methyl 4-IN-f 1 -(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoate

[0684] 2-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(R)-(3-methoxymethoxyphenyt)-2-(3 -(S)-methoxymethoxypyrroldin-1-yl)ethanol were prepared from (R)-1-(3-methoxymethoxyphenyt)-I,2-ethanediol-2-tosylate in 58% yield as a mixture according to the procedures similar to those described in Preparation 3. Title compound was prepared by reacting the mixture of 2-(S)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol with methyl 4-methylaminobenzoate in 54% yield according to the procedures similar to those described in Example 1 (i).

[0685]¹H NMR (270MHz, CDCl₃) δ7.88 (2H, d, J 8.8Hz), 7.23-7.19 (1Hz, m), 6.95-6.90(3H, m), 6.77(2H, d, J=8.8Hz), 5 13(2H, s), 5.12-5.08(1H, m), 4 58 (1H, d, J 6.6Hz) 4.53 (1H, d, J=6.6Hz), 4.224.15 (1H, m), 3.84 (3H, s), 3.45(3H, s), 3.28 (3H, s), 3.13-2.92(2H, m), 2.88 (3H, s), 2.90-2.84(1H, m), 2.75-2.66(1H, m), 2 61-2 50(2H, m), 2.06-1.99(1H, m), 1.83-1.74(1H, m).

[0686] (ii) 4- 1,N-[1-(R)-(33-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrroldin-1-yl-ethyl]-N-methylamino}benzoic acid

[0687] This was prepared from methyl 4-{N-[1-(R)-(3 -methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}benzoate in 91% yield according to the procedures similar to those described in Example 1 (ii).

[0688]¹H NMR (270MH, CDCl₃) δ7.91 (2H, d, J=3.8Hz), 7.30-7 12(1H, m), 6.98-6.84(3H, m), 6 82(2H, d, J=9.2Hz), 5.35-5 25(1H. m), 5.14(2H, s), 4.60(1H, d, J=7.0Hz) 4.55(1H, d, J=7.0Hz), 4.304 20(1H, m), 3.45(3H, S), 3.30(3H. s), 3.25-3 05(2H, m), 2.90(3H, s), 2.90-Z.60(4H, m), 2.20-2.00(1H, m), 1.90-1.80(1H, m).

[0689] (iii) 4-{N-[1-(R)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxyovrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide

[0690] This was prepared from 4-{N-[1-(R)-(3-methoxymethoxyphenyl)-2-(3)-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino)benzoic acid and n-propylamine in 71% yield according to the procedures similar to those described in Example 1 (iii).

[0691]¹H NMR (270MHz, CDCl₃) δ7.64(2H, d, J=8.8Hz), 7.28-7.18(K1, m), 6.98-6.88(3H, m), 6 78(2H, d, J=9.2Hz), 6.00-5 90(1H, m), 5.14(2H, s), 5 09(1H, r, J=7.7Hz), 4.58(1H, d, J=7.0Hz), 4.54(1H, d, J=7.0Hz), 4.254.12(1H, m), 3.46(31H, s), 3.45-3.35(2H, m), 3.29(31H, s), 3.08-2.96(2H, m), 2.92-2.80(11 m), 2.86(3H, s), 2.75-2.50(3H, m), 2.12-1.95(1H, m), 1.85-1.52(3H, m), 0.97(3H, t, J=7.3Hz).

EXAMPLE 76

[0692] Preparation of 4-{N-[1-(R)-(3-t-Butoxycarbonylmethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide

[0693] This was prepared from 4-{N-(1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzarnide in 11% over all yield accprding to the procedures similar to those described in Example 2 and Example 36.

[0694]¹H NMR (270Mz CDCl₃) 8 7.65(2H, d, J=8.8Hz), 7.267.20(1H, m), 6.92-6.89 (2H, m), 6.79(2H, d, J=9.2Hz), 6.79-6.75(1H, m), 6.01-5.92(1H, m), 5.11(1H, dd, J=7.0 7.2Hz), 4.47(2H, s), 4.26-4 17(1H, m), 3.45-3.35(21H, m), i.04(2H, d, J=7 3Hz), 2.98-2.91(1H, m), 2.81(3H, s), 2.69(1H, d, J=9.2Hz), 2.49(1H, dd, J=4.8, 9.-9Hz), 2.40-2.25(1H, m), 2.17-2.06(1H, m), 1.75-1.52(4H, m), 1.45(9H, s), 0.98(3EI, t, J7.3Hz)

EXAMPLE 77

[0695] Preparation of 4-{N-1-(R)-(3-Carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide

[0696] This was prepared from 4-{N-[1-(R)-(3-t-butoxycarbonylmethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide in 86% yield according to the procedures similar to those described in Example 3.

[0697] HCl salt:ligt brown solid. ¹H NMR (270MHz, DMSO-d6) δ10.55-10.15(1H, m), 8.32-8.24(1H, m), 7.91-7.80(2H, m), 7.34(1H, t, J=7.7Hz), 7 21-7 09(2H,m), 6 98-6.84(3H, m), 5.95-5.80(1H, m), 4.72(2H, s), 4.60-4.40(1H, m), 440-3 20(7H, m), 2 82(1.2H, s), 2.81(1.8H,s), 2.50-2.30(2H, m), 2.15-1.85(2H, m), 1 70-1 50(2H, m), 0 96(3H, t, J=7.3Hz)

[0698] IR(KBr) 3400, 1730, 1610cm⁻¹.

[0699] MS m/z: 456(M+H)⁺.

[0700] Anal. Calcd for C₂₅H₃₃N₃O₅·HCl·3.5H₂O:C, 54.10, H, 7.45, N, 7.57 Found. C, 54.49; H, 7.85; N, 7.76

EXAMPLE 78

[0701] Preparation of 3 -Fluoro-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl3-N-methylamino}-N′-propylbenzamide (i) Methyl 3-fluoro-4-{N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate

[0702] This was prepared from 2-(3-(S)-methoxymethoxypyrroldin-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin- 1-yl)-2-(R)-phenylethanol and methyl 3-fluoro-4-methylamninobenzoate in 52% yield according to the procedures similar to those described in Example 29 (i).

[0703]¹H NMR (270MHz, CDCl₃) 8 7.72-7.62(2H, m), 7.38-7.22 (5H, m), 6 81(1H, J=8 8Hz), 5.12-5.02(1H, m), 4.58 (1H, d, J=7.0Hz), 4 55(1H, d, I =7 OHz), 4.15-4.03(1H,m), 3.88(3H, s), 3.30(3H, s), 3 13-2 95(2T1l, m), 2 88-2.78(1H, m), 2 71(3H, d, J=0.7Hz), 2.67-2.45(3H, m), 2.05-1.90(1H, m), 1.75-1.60(1H, m)

[0704] (ii) 3-Fluoro-4-{N-[1-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylarnino}benzoic acid

[0705] This was prepared from methyl 3-fluoro-4-(N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}benzoate in 100% yield according to the procedures similar to those described in Example 1 (ii)

[0706]¹H NMR (270MHz, CDCl₃) δ7.63-7.54(2H, m), 7 38-7 22 (5H, m), 6.76(1H, t, J=8 4Hz), 5 27-5.17(1H,m), 4 61 (1H, d, J=7 0Hz), 4 58(1H. d, J=7.0Hz), 4.30-4.20(1H,m), 3.55-3 43(1H, m), 3.40-3.15(3H, m), 3.31(3H, s), 2.95-2.73(2H, m), 2.74(3H, s), 2.22-2.05(1H, m), 1.95-1 80(1H, m)

[0707] (iii) 3 -Fluoro-4-{N-[2-(3-(S-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylelthyl]-N-methyiamino}-N′-propylbenzamide

[0708] This was prepared from 3-fluoro4-{N-[2-(3-(S)-methoxymethoxypyrroldin-1-yl)-1-(S)-phenylethyl]-N-methylaminolbenzoic acid and n-propylarnine in 80% yield according to the procedures similar to those described in Example 1 (iii)

[0709]¹H NMR (270MHz, CDCl₃) 8 7.48 (1H, dd, J 1.8, 14 3H-z), 7.41-7.20(6H, m), 6.80(1H, t, J=8.8Hz), 6.08-6.00(lH,m), 5.03-4.92(1H,m), 4.58 (1H, d, J 7.0Hz), 4.54(1H, d, J=6.6Hz), 4.13-4 03(1H,m), 3 45-3.35(2H, m), 3.30(3H, s), 3.18-3.07(1H, in), 3.02(1H, dd, J=6.6, 12.8Hz), 2.83(1H, dd, J=6 2, 9 9Hz), 2.68(3H, s), 2.65-2.45((3H, m), 2.07-1.93 (1H, m), 1.75-1.55(3H, m), 0.99(3H, t, J=7.3Hz)

EXAMPLE 79

[0710] Preparation of 3-Fluoro-4-{N-[2-(3-(S)-hydrox-ypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide

[0711] This was prepared from 3-fluoro-4-(N-[2-(3-(S)-methoxymnethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide in 40% yield according to the procedures similar to those described in Example 2

[0712]¹H NMR (270MHz, free amine, CDCl₃) δ7.53 (1H, dd, J 2.2,14 3Hz), 7.41-7.24(6H, m), 6.83(1H, t, J=8.8Hz), 6.11-6 02(1H,m), 5.12-5.02(1H,m), 4224.13(1H,m), 3.45-3.35(2H, m), 3.35-3.23(1H, m), 3 GO(1H, dd, J=5.5, 12.5Hz), 2.92-2.73(2H, m), 268(3EH, s), 2.60-2.50(1H, m), 2.33-2.1S(1H, m), 2 13-1.95(1H, m), 1 90 (1H, br, s), 1.70-1.48(3H, m), 0.99(3H, t, J=7.3Hz)

[0713] Maleic acid salt:amorphous solid.

[0714] IR(KBr): 3350, 1620cm⁻¹.

[0715] MS 400(M+H)⁺

[0716] Anal. Calcd for C₂₃H₃₀N₃O₂F·C₄H₄O₄·0.5H₂O: C, 61.82; H, 6.72; N, 8.01 Found: C, 61.52; H,6.70, N, 8.02.

EXAMPLE 80

[0717] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2,2,3,3,-pentafluoropropyl)benzamide

[0718] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and 4-methylamino-N′-(2,2,3,3,3,-pentafluoropropyl)benzamide in 32% yield according to the procedures similar to those described in Example 1 (i).

[0719]¹H NMR (270MHz, CDCl₃) δ7.67(2H, d, J=8.8Hz), 7.34-7.25 (5H, m), 6 81(2H, d, J=9.2H1z), 6.30-6.13(1H, m), 5.15(1H, t, J=7.7Hz), 4.59 (1H, d, J=6.6Hz), 4.55(1H, d, J=6.6Hz), 4.-3-4.10(3H,m), 3 30(3H, s), 3.07-3.04(2H, m), 2.87(3H, s), 2.84-2.80(1H, m), 2.76-2.67(1H, m), 2.64-2.53(2H, m), 2.09-2.01(1H, m), I 77-1.70(1H, m)

EXAMPLE 81

[0720] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2,2,3,3,3,-pentafluoropropyl)benzamide

[0721] This was prepared from 4-{N-[2-(3-(S) methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino } -N′-(2,2,3,3,3,-pentafluoropropyl)benzamide in 97% yield according to the procedures similar to those described in Example 2.

[0722]¹H NMR (270MHz, free amine, CDCl₃) δ7.69(2H, d, J=8.8Hz), 7.36-7.26 (5H, m), 6.82(2H, d, J=8.8Hz), 6.20-6.16(1H, m), 5.16(1H, dd, J=5.5, 8.8Hz), 4.25-4.21(1H, m,), 4.14(2H, dd, J=6.2, 14.7Hz), 3.14(1H, dd, l=9.2, 12.8Hz), 3.04(1H, dd, J=5.9, 12.8Hz), 2.95-2.88(1H, m), 2.86(3H, s), 2.73(1H, d, J=9.5Hz), 2.57(1H, dd, J=4.8, 9.5Hz), 2.37-2.29(1H, m), 2.16-2.05(1H, m), 1.80-1.60(2H, m)

[0723] IR(neat): 3350, 1610cm⁻¹.

[0724] HCl salt. amorphous solid. MS m/z470(M−H)

[0725] Anal. Calcd for C₂₃H₂₆N₃O₂F₅·HCl·0.4CH₄O: C, 53.63; H, 5.44; N, 8.16 Found: C,53.90; H, 5.33 ; N,7.79.

EXAMPLE 82

[0726] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)- -(S)-phenylethyl]-N-methylanino}-N′-tert-amylbenzamide

[0727] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and 4-methylamino-N′-tert-amylbenzamide in 36% yield according to the procedures similar to those described in Example 1 (i).

[0728]¹H NNMR (270MHz, CDCl₃) δ7.60(2H, d, J=8.8Hz), 7 34-7.23 (5H, m), 6 7S( H, d, J=8.8Hz), 5.73-5.62(1H, m), 5.13(1H, dd, J=6.2, 8.4Hz), 4.60 (1H, d, J 7.0Hz), 4.55(1H, d, J=7.0Hz), 4.174.15(1H, m), 3 30(3H, s), 3 07-3 02(2H, m), 2 33(3H, s), 2.86-2.80(1H, m), 2.72-2.64(1I, m), 2.63-2.57(2H. m), 2.09-2.01(1H, m), 1.87-1.79(1H, m), 1.83(2H, q, J=7 3Hz), l.39(6H, s), 0.88(3H, t, J=7.3Hz).

EXAMPLE 83

[0729] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-tert-amylbenzamide

[0730] This was prepared from 4-{N-[2-(3-(S)-methoxymethoxypyrroliditn-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-tert-amylbenzamide in 88% yield according to the procedures similar to those described in Example 2.

[0731]¹H NMR (270MHz, free amine, CDCl₃) 8 7.62(2H, d, J=8.8Hz), 7.35-7.22 (5H, m), 6.79(2H, d, J=8.8Hz), δ5.73-5.63(1H, m), 5.14(1H, dd, J=5.9, 9.2Hz), 4.24-4.20(1H,m). 3.12(1H, dd, J=8.8, 12.8Hz), 3.03(1H, dd, J=5 9, 12 8Hz), 2 93 2 86(1H, m), 2.83(3H, s), 2.73(1H, d, J=9.9Hz), 2.56(1H, dd, ]=4 8, 9 5Hz), 2.36-2.27(1H, m), 2.14-2 04(1H, m), 1.83(2H, q, J=7.3Hz), 1.80-1.60(2H,m), i.40(6H, s), 0.88(3H, t, J=7.3Hz).

[0732] IR(neat) 3350, 1610cm⁻¹

[0733] HCl salt:amorphous solid. MS m/z:410(M+H)⁺

[0734] Anal. Calcd for C₂₅H₂₅N₃O₂·HCl·0.2CH₄O: C, 66.78, H, 8.16; N, 9.35 Found: C,66.67; H. 8.43, N,9.33.

EXAMPLE 84

[0735] Preparation of 4-{N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-tert-butylbenzamide

[0736] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolicin-1-yl)-2-(R)-phenylethanol and 4-methylarnino-N′-tert-butylbenzamide in 66% yield according to the procedures similar to those described in Example 1(i).

[0737]¹H NMR (270MHz, CDCl₃) δ7.61(2H, d, J=8 8Hz), 7 40-7.20 (5H, m), 6.78(2H, d, J=9.2Hz), 5.905.65(1H, m), 5.18-5.10(1H, m), 4.60 (1H, d, J=6.6Hz), 4 56(1H, d, J=7.0Hz), 4.24-4.14(1H,m), 3 30(3H, s), 3 10-2 98(2H. m), 2 90-2.78(1H, m), 2.84(3H s), 2.76-2.54(3H, m), 2.15-1.95(1H, m), 1 80-1 60(IFL m), I 45(9H, s).

EXAMPLE 85

[0738] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-tert-butylbenzamide

[0739] This was prepared from 4-{N-[2-(3-(S)-rrethoxymethoxypyrrolidin-1-yl-1-(S)-phenylethyl]-N-methylamino}-N′-tert-butylbenzamide in 52% yield according to procedures similar to those described in Example 2.

[0740]¹H NMR (270MHz, free amine, CDCl₃) δ7.62(2H, d, J=8.8Hz), 7.35-7.24 (5H, m), 6.79(2H, d, J=9.2Hz), 5.83-5.77(1H, m), 5 14(iH, dd, J=5 5, 8 8Hz), 4 26-4 18(1H, m), 3.13(1H, dd, J=9.2, 12.8Hz), 3.03(1H, dd, J=5 9, 12.8Hz), 2.92-2.86(1H, m), 2.83(3H, s), 2.74(11H, d, J=9.9Hz), 2.55(1H, dd, J=4.8, 9.9Hz), 2.36-7(1H, m), 2.11-2.08(1H, m), 1.72-1.54(2H, m), 1.45(9H, s).

[0741] IR(neat). 3350, 1610cm⁻¹.

[0742] HCl salt: amorphous solid. MS m/z:396(M+H)⁺

[0743] Anal. Calcd for C₂₄H₃₃N₃₃O₂·HCL·1.2H₂O C, 63.55; H, 8.09; N, 9.26 Found: C,63.34; H,7.93; N,9.01.

EXAMPLE 86

[0744] Preparation of 5-(N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl,-N-methylamino}-N′-propylpicolinamide

[0745] This was prepared from 2-(3-(S)-methoxymnethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3 -(S)-methoxymethoxypyrrolidin-1-y)-2-(R)-phenylethanol and 5-methylamino-N′-propylpicolinamide in 24% over all yield according to the procedures similar to those described in Example 1 (i) and Example 2.

[0746]¹HNMR(27MHz, free amine, CDCl₃) δ8.12(11H, d, J=3.3Hz), 8 02(1H, d, J=8.8Hz), 7.82-7.74(1H, rm), 7.38-7.24 (5H, m), 7.13(1EL dd, J=3.3, 8.8Hz), 5 IO(1H, dd, J=5.5, 9.5Hz), 4.304.20(1H, m), 3.45-3.35(2H, m), 3 17(1H, dd, J=9.5, 12 8Hz), 3 01(1H, dd, J=5.5, 12.8Hz), 2.95-2.84(1H, m), 2.91(3H, s), 2 70(1H, d, J=9.2Hz), 2.61(1H, dd, J=4.8, 9.5Hz), 2.42-2.30(11, m), 2.18-2.02(1H, m), 1.80-1.55(4H,m), 0.98(3H, t, J=7.3Hz).

[0747] Fumaric acid salt: amorphous solid. 1R(KBr) 3400, 1650cm⁻¹. MS n/z:383(M+H)⁺ Anal. Calcd for C₂₂H₃₀N₄O₂·C₄H₄O₄·0.5H₂O: C, 61.52; H, 6.95, N, 11.04 Found C, 61.75; H, 7.09; N, 10.95.

EXAMPLE 87

[0748] Preparation of 4-{N-Hydroxy-N-[2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino}-N′-propylbenzamide

[0749] This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 4-hydroxyaminobenzoate in 33% over all yield according to the procedures similar to those described in Example 1 (i),(ii) and (iii).

[0750]¹H N (270MHz, CDCl₃) δ7.55(2H, d, J=8.8Hz), 7.43-7 18 (5H, m), 6.90(2H, d, J=8.8Hz), 6.05-5.95(1H, m), 4.87(1H, dd, J=5.1, 10.3Hz), 4.63 (IK d, J=7.0Hz), 4.60(1H, d, J=7.0Hz), 4.30-4.20(1H, m), 3.58-3 46(2H, m), 3.43-3 25(2H, m), 3.35(3H, s), 2.95-2.50(4H, m), 2.20-1.80(2, m), 1.70-1.50(2H, m), 0 96(3H, t, J=7.3Hz).

EXAMPLE 88

[0751] Preparation of 4-{N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino}-N′-propylbenzamide

[0752] This was prepared from 4-(N-hydroxy-N-[2-(3-(S)-methoxyrnethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino}-N′-propylbenzamide in 63% yield according to the procedures similar to those described in Example 2.

[0753]¹H NM (2/0MHz, free amine, CDCl₃) δ8.86(1H, s), 8.18-8.08(1H,m), 7.64(H, d, J=8.8Hz), 7.42(2H, d, J=6.6Hz). 7 27-7 12 (3H, m), 7.07(2H, d, J=8.8Hz), 4.96(1H, dd, J=6.6, 7.3Hz), 4.62 (1H, d, J 4 8Hz), 4.15-4.05(1H,m), 3 20-3.10(2H, m), 3.07-2.92(2H, m), 2.74(1H, dd, J-6.95Hz), 2.56(2H, t, J=7 3Hz), 2 36(1H, dd. 3 J=4 9.5Hz), 2.00-1.80(1H, m), 1.55-1 40(3H. m), 0.86(3H, t, J=7.3Hz).

[0754] Fumaric acid salt:amorphous solid.

[0755] IR(KBr): 3300, 1630cm⁻¹.

[0756] MS m/z:384(M+H)⁺

[0757] Anal. Calcd for C₂₂H₂₉N₃O₃·C₄H₄O₄·0.5H₂O: C, 61.40, H, 6.74; N, 8.26 Found: C, 61.40; H,6.78 N, 8 08.

EXAMPLE 89

[0758] Preparation of 4-{N-[2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamide

[0759] This was prepared from 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S-phenylethyl]-N-methylamino)benzoic acid and (S)-(+)-1-amino-2-propanol in 38% yield according to the procedures sirilar to those described in Example 1 (iii).

[0760]¹H NMR (270MHz, free amine, CDCl₃) δ7.67(2H, d, J=8. gHz), 7.35-723 (5H, m, 6.78(2H, d, J=8Hz), 6.47-6.42 (1H, m), 5.214.94(1H, m), 5.11(1H, dd, J=6.2 8.4Hz), 4.03-3.97(1H, m), 3.64-3.56(1H, m), 3.35-3 25(1H, m), 3.16-3.01(2H, m) 2.89-2.76(3H, m), 2.87(3H, s), 2.58-2.50(1H, m), 2.11-1.90(1H, m), 1.76-1 55(2H, m), 1.22(3H, d, J=6.6Hz)

[0761] Fumaric acid salt: amorphous solid.

[0762] MS m/z: 400(M+H)⁺

[0763] Anal. Calcd for C₂₃H₃₀N₃O₂F·C₄H₄O₄·0.8CH₄O: C, 61.70; H, 6.93; N, 7.76 Found : C, 61.52, H, 6.59; N,7.64.

EXAMPLE 90

[0764] Preparation of 2-Chloro-4-{N-[1-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide

[0765] This was prepared from 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-fluoropyrrolidin- -yl)-2-(R)-phenylethanol and 2-chloro-4-methylamino-N′-propylbenzamide in 13% yield according to the procedures similar to those described in Example 1 (i).

[0766]¹H NMR (270MHz, free amine, CDCl₃) δ7.75(1H, d. J=8 4Hz), 7.38-7.20 (5H, m), 6.78-6.70(2H, m), 6.58-6.50 (1H, m), 5.25-4.95(1H, m), 5 04(1H, dd, l=6.2, 8.4Hz, 3.50-3.37(2H, m), 3.12(1H, dd, J=9.2, 12 8Hz), 3.03(1H, dd, J=5 9, 12 8Hz), 2.90-2.75(2H, m), 2.85(3H, s), 2.60-2 50(1H, m), 2 17-1.85 (2H, m), 1 70-1 55(3H, m), 0.99(3EK t, J=7.3Hz).

[0767] Fumaric acid salt: amorphous solid.

[0768] MS m/z: 418(M+H)⁺

[0769] Anal. Calcd for C₂₃H₂₉N₃OFCl·C₄H₄O₄·0.1H₂O: C, 60.52; H, 6.25; N, 7.84 Found:C,60.16;H,661;N,7.64.

EXAMPLE 91

[0770] Preparation of 4-{N-[2-(3-S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-hydroxyamino}-N′-propylbenzamide

[0771] This was prepared from 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol and 4-hydroxyamino-N′propylbenzamide in 56% yield according to the procedures similar to those described in Example 1 (i).

[0772] HCl salt: mp: 195-200° C.

[0773]¹H NMR (270MHz DMSO) δ10.67(1H, br s), 9 35-9 20(1H, m), 8.30-8.20(1H, m), 7.70(2H, d, J=8.4Hz), 7 50-7.15 (7H, m), 5 70-5 35(2H, m), 4.25-3.30(6H, m), 3.5-3.10(2H, m), 2.70-2.10(2H, m), 1 60-i.40(2H, m), 0 86(3H, t, J=7.3Hz)

[0774] IR(KBr): 1600 cm⁻¹

[0775] MS m/z: 384(M-H)

[0776] Anal. Calcd for C₂₂H₂₈N₃O₂F·HCl C, 62.63; H, 6.93; N, 9.96 Found C, 62.23; H, 7.10, N,9.79

EXAMPLE 92

[0777] Preparation of 5-{N-[2-(3-(S)-Fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylpicolinamide

[0778] This was prepared from 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-flucropyrrolidin-1-yl)-2-(R)-phenylethanol and 5-methylaino-N′-propylpicolinamide in 26% yield according to the procedures similar to those described in Example 1 (i).

[0779]¹H NMR (270MHz, free amine, CDCl₃) δ8.10(1H, d, S=2.9Hz), 8.01(1H, d, J=8.8Hz), 7.82-7.74(1H, m), 7.38-7.24 (5H, m), 7. I(1H, dd, J=2 9, 8.8Hz), 5.23-4.94(1H, m), 5.07(1H, dd, J=5.9, 9.5Hz), 3.45-3.35(2H, m), 3 18(1H, dd, J=9 5, 12.8Hz), 3.03(1 H, dd, J=5.9, 12.8Hz), 2.95-2.75(2H, m), 2.93(3H, s), 2.60-2.50(1H, m), 2.18-1.90(23 m), 1.70-1.55(3H, m), 0.98(3H, t, J=7.3Hz).

[0780] Fumaric acid salt:amorphous solid.

[0781] 1R(KBr): 1650cm⁻¹.

[0782] MS m/z:385(M+H)⁺

[0783] Anal. Calcd for C₂₂H₂₉N₄OF·C₄H₄O₄·0.6H₂O C, 61.07; H, 6.74; N, 10.96 Found: C, 60.87; H, 6.35; N, 10.89.

EXAMPLE 93

[0784] Preraration of 4-{N-Methylamino-N-[2-(3-pyrrolin-1-yl)-1-(S)-phenylethyl]}-N′-propylbenzamide

[0785] This was prepared from 2-(R)-phenyl-2-(3-pyrrolin-1-yl)ethanol and 4-methylamino-N′-propylbenzamide in 12% yield according to the procedures similar to those described in Example 1 (i).

[0786]¹H NMR (270Hz, free amine, CDCl₃) δ7.65(2H, d, J=9.2Hz), 7.35-7.24 (5H m), 6.80(2H, d, J=9 2Hz), 5.97 (1H,br s), 5 72(2H, s), 5.12(1H, dd, J=7.0, 7 7Hz), 3.58-3.49(4H, m), 3.38(2H, dd, J=5.9, 7 3Hz), 3.25-3.21(2H, m), 2.86(3H, s), l 61(2H, dd, J=7.3, 14.7Hz), 0.97(3H, t, J=7.3Hz)

[0787] lR(neat): 2950, 1650cm⁻¹.

[0788] HCI salt:amorphous solid.

[0789] MS m/z: 363 (M⁺)

[0790] Anal. Calcd for C₂₃H₂₉N₃O·HCl·0.1CH₄O·0.9H₂O: C, 66.16; H, 7.74; N, 10.02. Found: C, 66.56; H. 1.64; N,9.65 .

EXAMPLE 94

[0791] Preparation of 4-{N-[2-(3-(R)-fluoropyrrolidine]-yl)-1-(S)-phenylethy]-N-methylamino}-N′-propylbenzamide

[0792] This was prepared from 2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(R)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol and 4-methylamino-N′-propylbenzamide in 47% yield according to the procedures similar to those described in Example 1 (i).

[0793]¹H NMR (270MHz, free amine, CDCl₃) δ7.67(2H, d, J=8.8Hz), 1.34-7.24 (5H, m), 6.79(2H, d, J=8.8Hz), 6.13 (1H, br. s), 5.25-4.95(1H, m), 5.13(1H, dd, J=6.2, 8.4Hz), 3.41-3.34(2H, m), 3.17-3.05(2H, m), 3.02-2.77(3H, m), 2.82(3H, s), 2.59-2 51(1H, m), 2.09-1.91(2H, m), 1.72-1.54(2H, m), 0.95(3H, t, J=7.3Hz)

[0794] HCl salt:amorphous solid.

[0795] MS m/z: 383(M⁺)

[0796] Anal. Calcd for C₂₃H₃₀N₃OF·HCl 0.5H₂O: C, 64.40; H, 7.52; N, 9.80 Found C, 64.51; H, 7.74; N, 9.46,

EXAMPLE 95

[0797] Preparation of 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenyletlthyl]-N-methylamino}-N′-propylbenzamide

[0798] This was prepared from 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylethanol and 2-(3-(S)-fluoropyrrolidin-1-yl)-2-(S)-phenylethanol and 4-methylarnino-N′-propylbenzamide in 28% yield according to the procedures similar to those described n Example 1 (i).

[0799]¹H NMR (270MHz, fee amine, CDCl₃) δ7.65(2H, d, J=8.4Hz), 7.30-7.24 (5H, m). 6.80(2H, d, J=8.4Hz), 6.00 (1H, br. s), 5.254.95(2M, m), 3.43-3.36(2H, m), 3.13-3.07(2H, m), 3.01-2.89(2H, m), 2.83(3H, s), 2.58-2.55(1H, m), 2.10-2.00(1H, m), 2.00-1.92(1H, m), 1.73-1.55(3H, m), 0.97(3K, t, J=7.3Hz)

[0800] HCl salt:amorphous solid.

[0801] MS m/z:383(M⁺)

[0802] Anal. Calcd for C₂₃H₃₀ ₃OF·HCl·2H₂O C, 60.58; H, 7.74; N, 9.21 Found: C, 60.59: H, 7.36; N, 9.23.

EXAMPLE 96

[0803] Preparation of 4-{N-[2-(3-(S)-Chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′′-propylbenzamide

[0804] This was prepared from 2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol and 4-methytamino-N′-propylbenzamide in 40% yield according to the procedures similar to those described in Example 1 (i). ¹H NR (270MHz free amine, CDCl₃) δ7.68(2H, d, J=8.8Hz), 7.33-7.27 (5H, m), 6.78(2H, d, J=8.8Hz), 6.23 (1H, br, s), 5.08(1H, dd, J=7.3, 7.7Hz), 4.30-4.25(1H, m), 3.40-3.33(2H, m), 3.13-3.08(3H, m), 2.84(3H, s), 2.81-2.65(3H, m), 2.36-2 22(1H, m), 2.02-1.95(1H, m), 1.63-1.53(2H, m), Q 94(3H, t, J=7.3Hz)

[0805] HCl salt amorphous solid.

[0806] MS rnlz: 399(M⁺)

[0807] Anal. Calcd for C₂₃H30N₃OCl·HCl·2.5H₂O: C, 57.38; H, 7.54; N, 8.73. Found C,57.10, H, 7.42, N,8.48

EXAMPLE 97

[0808] Preparation of 4-{N-[2-C3-(S)-Chloroporroiidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamide

[0809] This was prepared from ²-(³-(S)-chloropyrrolhdin-1-yl)-(S)phenylethanol and 2-(3-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol and 4-methylamino-N′-(2-(S)-hydroxypropyl)benzamide in 45% yield according to the procedures similar to those described in Example 1 (i).

[0810]¹H NMR (270NMHz, free amine, CDCl₃) δ7.68(2H, d, J=9.2Hz), 7.35-7.28 (5H, m), 6.79(2H d, J=8 SHz), 6.52 (1H, br. s), 5 !O(1H, t, J=7Hz), 4 32-4 27(1H, m), 4.02-3.97(1H, m), 3.64-3.56(1H, m), 3 35-3 24(1H, m), 3.14-3.10(3H, m), 2.86(3H, s), 2.82-2.76(2H, m), 2.74-2.69(iH, m), 2.38-2.27(1H, m), 2.05-1.80(2H, m), 1.22(3H, d, J=6.2Hz)

[0811] HCl salt:amorphous solid.

[0812] MS rrl/z: 415(M⁺)

EXAMPLE 98

[0813] Preparation of 4-{N-[2-(3-(S)-Chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(R)-hydroxypropyl)benzamide

[0814] This was prepared from 2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S )-chloropyrrolidin-1-yl)-2-(R)-phenylethanol and 4-methylamino-N′-(2-(R)-hydroxypropyl)benzamide in 44% yield according to the procedures similar to those described in Example 1 (i).

[0815]¹H NMR (270MHz, free amine, CDCl₃) δ7.68(1H, d, J=9.2Hz), 7.35-7.23 (5H, m), 6.79(2H, d, J=9.2Hz), 6.53 (1H, br s), 5 1 I(1H, t. J=7 3Hz), 4 33-4 27(11H, m), 4.03-3.98(1H, m), 3.64-3.56(1H, m), 3 35-3.25(1H, m), 3.16-3.1 (1H, m), 3.12(2H, d, J=7.3Hz), 2.85(3H, s), 2.83-2.71(3H, m), 2.36-2.27(1H, m), 2.04-1.98(1H, m), 1.22(3H, d, J=6.2Hz)

[0816] HCl salt:amorphous solid.

[0817] MS m/z: 416(M+H)⁺

[0818] Anal. Calcd for C₂₃H₃₀N₃O₂Cl·HCl·H₂O: C, 58.72; H, 7.07; N, 8.93 Found: C, 58.56; H, 7.00; N,8.76.

EXAMPLE 99

[0819] Preparation of 4-{N-[2-(3-Oxopyrrolidin- 1 -yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide

[0820] To a stirred solution of oxalylchloride(0.26 ml, 3.0 mmol) in CH₂Cl₂(15 ml) was added a solution of DMSO(0.29 ml, 4.0 mmol) in CH₂Cl₂(1 ml) at −78° C. The reaction mixture was stirred for 10min and a solution of 4-{N-(2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide( 573 mg, 1.5 mmol) in CH₂Cl₂(5 ml) was added and stirring was continued for an additional 15 rrin at −78° C. 60 min at −45° C. Triethylamine(1.6 ml, 110 mmol) was added and then the reaction mixture was allowed to warm to room temperature. Saturated NH₄CL aqueous solution was added and extracted with AcOEt. The extract was washed with water and brine, dried(Na₂SO₄), and concentrated to give brown oil, which was purified by column chromatography (silica gel. 70 g, CH₂Cl₂/MeOH: 50/1-40/1) to give 195 mg(34%) of paie yellow oil.

[0821]¹H NMR (270MHz, free amine, CDCl₃) δ7.66(2H, d, J=9.2Hz), 7.36-7.25 (5H, m), 6.80(2H, d, J=9.2Hz), 6.01 (1H, br. s), 5 17(1H. t. J=7.3Hz), 3.43-3.36(2H, m), 3.17 3.13(2K m), 3.07-2.92(4H, m), 2.85(3H, s), 2.35(2H, t, J=7.0Hz), 1.6-1.53(2H, m), 0.97(3H, t, J=7.7Hz).

[0822] HCl salt amorphous solid.

[0823] MS m/z: 379(M⁺)

EXAMPLE 100

[0824] Preparation of 4-{N-[2-(3-(S)-Hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide

[0825] 4-(N-[2-(3-(S)-Methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzanide was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and 4-methylamino-N′-propylbenzamide according to the procedures sirrillar to those described in Example 1 (i). Title compound was prepared from 4-{N-[2-(3-(S)-methoxyqmethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide in 65% over all yield according to the procedures similar to those described in Example 2. The title compound was the same as one obtained in Example

[0826]¹H NMR (270MHZ, free amine, CDCl₃) δ7.66(2H, d, J=8.8Hz), 7.40-7.20(5H, m) 6.80(2H, d, J=9.2Hz), 6.05-5.90(11, m), 5.14(1H, dd, J=5.9, 9.2Hz), 4.28-4.16(1H, m), 3.46-3.32(2H, m), 3.12(1H, dd, J=9.2, 1.3Hz), 3.03(1H, dd, J=5.9, 12 8Hz), 2.95-2.80(1H,m), 2.83(3H, s), 2.72(11, d, J=9.5Hz), 2.56(1K, dd, J=4.8, 9.9Hz), 2.33(1H, ddd, J=6.2, 8.8, 8.8Hz), 7.18-2.00(1H, m), 1.89(1H, br. s), 1.70-1.50(3H, m), 0.97(3H, t, J=7.3Hz)

[0827] HCl salt:amorphous solid. MS m/z;382(M+H)

[0828] Anal. Calcd for C₂₃H₃₁N₃O₂·HCl·1.5H₂O·CH₄O: C, 60.43; H, 8.24, N, 8.81 Found: C,60.23; H,8.62; N,9.03

[0829] The chemical structures of the compounds prepared in Examples 1 to 100 are summarized in the following tables. In the tables, H- represents hydrogen-, Me-, Et-, Pr-, Bu-, Pe- and Am- represent methyl, ethyl, propyl, butyl, pentyl and amyl respectively; F- and Cl- represent fluorine and chlorine respectively; All-, and Prp- represent altyl and propargyl respectively; MeO-and EtO- represent methoxy and ethoxy respectively; HO- represents hydroxy; Car- represents carboxy; Ph-, Py-, Th- and Bn- represent phenyl, pyridyl, thienyl and benzyl respectively; MOM-, t-Boc-, 2-THP- and TBDMS- represent methoxymethyl, t-butoxycarbonyl, tetrahydropyran-2-yl and r-butyldimethylsilyl respectively; tri-F-Pr-, penta-F-Pr- and 2-HO-Pr-represent 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl and 2-hydroxypropyl respectively; O=represents oxo; and cyc represents cyclic. TABLE 1

Ex.-# A At¹ Ar² R¹ R² R³  1 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- Pr— H—  2 (S)-HO— (S)-Ph- 1,4-Ph- Me- Pr— H—  3 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- Me- H—  4 (S)-HO— (S)-Ph- 1,4-Ph- Me- Me- H—  5 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- Et- H—  6 (S)-HO— (S)-Ph- 1,4-Ph- Me- Et- H—  7 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- Bu- H—  8 (S)-HO— (S)-Ph- 1,4-ph- Me- Bu- H—  9 (S)-2-THP-O— (S)-Ph- 1,4-Ph- Me- Pe- H— 10 (S)-HO— (S)-Ph- 1,4-Ph- Me- Pe- H— 11 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- i-Pr— H— 12 (S)-HO— (S)-Ph- 1,4-Ph- Me- i-Pr— H— 13 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- Ph- H— 14 (S)-HO— (S)-Ph- 1,4-Ph- Me- Ph- H— 15 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- 2-Cl-Bn- H— 16 (S)-HO— (S)-Ph- 1,4-Ph- Me- 2-Cl-Bn- H— 17 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- Me- Me- 18 (S)-HO— (S)-Ph- 1,4-Ph- Me- Me- Me- 19 (S)-2-THP-O— (S)-Ph- 1,4-Ph- Me- Pr— Me- 20 (S)-HO— (S)-Ph- 1,4-Ph- Me- Pr— Me- 21 (S)-MOM-O— (S)-Ph- 1,3-Ph- Me- Pr— H— 22 (S)-HO— (S)-Ph- 1,3-Ph- Me- Pr— H— 33 (S)-MOM-O— (S)-3-MOM-O-Ph- 1,4-Ph- Me- Pr— H— 34 (S)-HO— (S)-3-HO-Ph- 1,4-Ph- Me- Pr— H— 35 (S)-HO— (S)-3-MeO-Ph- 1,4-Ph- Me- Pr— H— 36 (S)-HO— (S)-3-t-Boc-MeO— 1,4-Ph- Me- Pr— H— 37 (S)-HO— (S)-3-Car-Meo-Ph- 1,4-Ph- Me- Pr— H— 38 H— (S)-Ph- 1,4-Ph- Me- Pr— H— 40 (S)-MOM-O— (S)-Ph- 2,5-Th- Me- Pr— H— 41 (S)-HO— (S)-Ph- 2,5-Th- Me- Pr— H— 42 (S)-MOM-O— (S)-Ph- 1,4-Ph- H— Pr— H— 43 (S)-HO— (S)-Ph- 1,4-Ph- H— Pr— H— 44 (S)-MOM-O— (S)-3-Cl-Ph- 1,4-Ph- Me- Pr— H— 45 (S)-HO— (S)-3-Cl-Ph- 1,4-Ph- Me- Pr— H— 46 (S)-F— (S)-Ph- 1,4-Ph- Me- Pr— H— 47 (S)-MOM-O— (R)-Ph- 1,4-Ph- Me- Pr— H— 48 (S)-HO— (R)-Ph- 1,4-Ph- Me- Pr— H— 51 (S)-TBDMS-O— (S)-Ph- 1,4-Ph- Me- EtO- H— 52 (S)-HO— (S)-Ph- 1,4-Ph- Me- EtO- H— 55 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- 3-HO—Pr— H— 56 (S)-HO— (S)-Ph 1,4-Ph- Me- 3-HO—Pr— H— 57 (S)-MOM-O— (S)-Ph 1,4-Ph- Me- 2-(R)-HO—Pr— H— 58 (S)-HO— (S)-Ph- 1,4-Ph- Me- 2-(R)-HO—Pr— H— 59 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- i-Bu- H— 60 (S)-HO— (S)-Ph- 1,4-Ph- Me- i-Bu- H— 61 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- All- H— 62 (S)-HO— (S)-Ph- 1,4-Ph- Me- All- H— 63 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- cyc-Pr— H— 64 (S)-HO— (S)-Ph- 1,4-Ph- Me- cyc-Pr— H— 65 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- (S)-sec-Bu- H— 66 (S)-HO— (S)-Ph- 1,4-Ph- Me- (S)-sec-Bu- H— 67 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- (R)-sec-Bu- H— 68 (S)-HO— (S)-Ph- 1,4-Ph- Me- (R)-sec-Bu- H— 69 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- Prp- H— 70 (S)-HO (S)-Ph- 1,4-Ph- Me- Prp- H— 71 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- tri-F—Pr— H— 72 (S)-HO— (S)-Ph- 1,4-Ph- Me- tri-F—Pr— H— 73 (S)-MOM-O— (S)-Ph 1,4-Ph Me 2-(S)-HO—Pr H 74 (S)-OH (S)-Ph- 1,4-Ph- Me- 2-(S)-HO—Pr— H— 75 (S)-MOM-O (R)-3-MOM-O-Ph- 1,4-Ph- Me- Pr— H— 76 (S)-HO— (R)-3-t-Boc-Meo-Ph- 1,4-Ph- Me- Pr— H— 77 (S)-HO— (R)-3-Car-Meo-Ph- 1,4-Ph- Me- Pr— H— 80 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- penta-F—Pr— H— 81 (S)-HO— (S)-Ph- 1,4-Ph- Me- penta-F—Pr— H— 82 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- t-Am- H— 83 (S)-HO— (S)-Ph- 1,4-Ph- Me- t-Am- H— 84 (S)-MOM-O— (S)-Ph- 1,4-Ph- Me- t-Bu- H— 85 (S)-HO— (S)-Ph- 1,4-Ph- Me- t-Bu- H— 87 (S)-MOM-O— (S)-Ph- 1,4-Ph- HO— Pr— H— 88 (S)-HO— (S)-Ph- 1,4-Ph- HO— Pr— H— 89 (S)-F— (S)-Ph- 1,4-Ph- Me- 2-(S)-HO—Pr— H— 91 (S)-F— (S)-Ph- 1,4-Ph- HO— Pr— H— 94 (R)-F— (S)-Ph- 1,4-Ph- Me- Pr— H— 95 (S)-F— (R)-Ph- 1,4-Ph- Me- Pr— H— 96 (S)-Cl- (S)-Ph- 1,4-Ph- Me- Pr— H— 97 (S)-Cl- (S)-Ph- 1,4-Ph- Me- 2-(S)-HO—Pr— H— 98 (S)-Cl- (S)-Ph- 1,4-Ph- Me- 2-(R)-HO—Pr— H— 99 O═ (S)-Ph- 1,4-Ph- Me- Pr— H— 100  (S)-HO— (S)-Ph- 1,4-Ph- Me- Pr— H—

[0830] TABLE 2 Example 23

Example 24

Example 25

Example 26

Example 27

Example 28

Example 29

Example 30

Example 31

Example 32

Example 39

Example 49

Example 50

Example 53

Example 54

Example 78

Example 79

Example 86

Example 90

Example 92

Example 93 

1. A compound of the following formula:

and the salts thereof, wherein A is hydrogen, halo, hydroxy, C₁-C₆ alkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, oxo, OY wherein Y is a hydroxy protecting group, or absent; the broken line represents an optional double bond with proviso that if the broken line is a double bond, then A is absent; Ar¹ is phenyl optionally substituted by one or more substituents selected from halo, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy-C₁-C₄ alkoxy, CF₃, carboxy-C₁-C₄ alkoxy and C₁-C₄ alkoxy-carbonyl-C₁-C₄ alkoxy; Ar² is aryl or he~eroaryl selected from phenyl, naphthyl, pyridyl, thienyl, furyl, pyrrolyl and pyrimidyl, the aryl or heteroaryl being optionally substituted by one or more substituents selected from halo, hydroxy, amino, nitro, carboxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylarino, di C₁-C₄ alkylamino, halo C₁-C₄ alkyl, C₁-C₄ alkylthio and sulfonyl methyl; R¹ is hydrogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy or OY wherein Y is a hydroxy protecting group; and R² and R³ are independently selected from hydrogen, hydroxy, C₁-C₇ alkyl optionally substituted by one or more hydroxy or halo, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₇ alkoxy, phenyl optiontlly substituted by halo, phenyl C₁-C7 alkyl, halo substituted phenyl C₁-C₇ alkyl, and (CH₂)nX-R⁴ wherein n is one or two; X is O. NH or S and R⁴ is C₁-C₃ alkyl, or when Ar² is phenyl, —Ar²—C(=O)—N(R²)— is a phthalimide group and R³ is C₁-C₇ alkyl, or R² and R³, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by C₁-C₃ alkyl or haio
 2. A compound according to claim 1 , wherein A is hydrogen, halo, hydroxy, oxo or OY, or if the broken line is a double bond, then A is absent; Ar¹ is phenyl optionally substituted by one to three substituents selected from halo, hydroxy, C₁-C₄ alkoxy, carboxy C₁-C₄ alkoxy and C₁-C₄ alkoxy-carbonyl-C₁-C₄ alkoxy; Ar² is phenyl, pyridyl or thienyl, optionally substituted by one to two halo or C₁-C₄ alkoxy; R¹ is hydrogen, hydroxy or C₁-C₄ alkyl; and R² and R³ are independently selected from hydrogen, C₁-C₇ alkyl optionally substituted by one or more hydroxy or halo, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ alkoxy phenyl and halo substituted phenyl C₁-C₇ alkyl, when Ar² is phenyl, —Ar²—C(=O)—N(R²)— is a phthaliride group and R³ is C₁-C₇ alkyl, or R² and R³, together with the nitrogen atom to which they are attached, form a pyrrolidine or morpholne ring.
 3. A compound according to claim 2 , wherein A is hydrogen, fluorine, chlorine, hydroxy or OY wherein Y is methoxymethyl or tetrahydropyranyl; or if the broken line is a double bond, then A is absent; Ar¹ is phenyl optionally substituted by chlorine, hydroxy, methoxy or carboxymethoxy; Ar² is phenyl, pyridyl or thienyl, optionally substituted by chlorine, fguorine or methoxy; R¹ is C₁-C₄ alky; R² is C₁-C₇ alkyl optionally substituted by hydroxy or fluorine, C₂-C₆ alkenyl, halo substituted phenylmethyl or phenyl; and R³ is hydrogen or methyl; or R² and R³, together with the nitrogen atom to which they are attached, foam a pyrrolidine or morpholine ring.
 4. A compound accroding to claim 3 , wherein A is hydroxy, fluorine or chlorine; or if the broken line is a double bond, then A is absent; Ar¹ is phenyl optionally substituted by carboxymethoxy; Ar² is phenyl optionally substituted by methoxy or pyrldvi; R¹ is C₁-C4 alkyl; R² is C₁-C₇ alkyl optionally substitute by hydroxy; and R³ is hydrogen.
 5. A compound according to claim 4 selected from 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-2-methoxy-N′-propylbenzamide; 6-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylnicotinamide; 4-{N-[1-(S)-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamide; 5-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylaniuno}-N′-propylpicolinamide; 4-{N-methylamino-N-[2-(3-pyrrolin-1-yl)-1-(S)-phenylethyl]}-N′-propylbenzamide; and 4-{N-[2-(3-(S)-chloropyrrolidin-1-yl)-1-S)-phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamide.
 6. A compound according to claim 3 selected from 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-isopropylbenzamide; 3-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide; ²-chloro-4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino)-N′-propylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrroiidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-3-methoxy-N′-propylbenzamide; 3-chloro-4-{N-[2-3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[1-(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(3-methoxyphenyl)-ethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[1-(S)-phenyl-2-(pyrrolidin-1-yl)ethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[1-(S)-(3-corophenyl)-2-(3-(S)-hydroxyyrrolidin-1-yl)-ethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-pyrrolidinebenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-morpholinebenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(R)-hydroxypropyl)benzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-isobutylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-allylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(3,3,3,-trifluoropropyl)benzamide; 3-fluoro-4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenytethyl)-N-methylamino}-N′-(2,2,3,3,3,-pentafluoropropyl)benzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylanino}-N′-tert-amylbenzamide; 5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylpicolinamide; 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-(S)-hydroxypropyl)benzamide; 2-chloro-4-{N-[2-(3-(S)-fluoropyrroiidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide; and 4-{N-[2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino-N′-propylbenzamide.
 7. A compound according to claim 2 selected from 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-methylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-ethylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-butylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-pentylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-phenylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(2-chlorobenzyl)benzamide; 4-{N-[2-(3-(S)-hydroxypyrrofidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-dimethylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-methyl-N′-propylbenzamide; 5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propyl-2-thiophenecarboxamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino} -N′-propylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylphthalimide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-ethoxybenizamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(3-hydroxypropyl)benzamide, 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-cyclopropylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(S)-sec-butylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-(R)-sec-butylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino} -N′-propargylbenzamide; 4-{N-[1-(R)-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]1-N-methylamino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-tert-butylbenzamide; 4-{N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)- 1-(S)-phenylethyl]amino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-hydroxyamino}-N′-propylbenzamide; 4-{N-[2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N′-propylbenzamide, 4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}-N′-propylbenzamide; 4-{N-[2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)phenylethyl]-N-methyl amino}-N′-(2-(R)-hydroxypropyl)benzamide; and 4-{N-[2-(3-oxopyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino }-N′-propylbenzamide.
 8. A pharmaceutical composition for the prevention or treatment of a medical condition for which agoriist activity toward opioid kappa receptor is needed, in a mammalian subject, which comprises a therapeutically effective amount of a compound according to claim 1 , and a pharmaceutically inert carrier.
 9. A pharmaceutical composition according to claim 8 , which is usefiul as an analgesic, anesthetic, anti-inflammatory or neuroprotective agent, or usefl in the treatment of arthritis, stroke or finctional bowel disease.
 10. A method for the treatment of a medical condition for which agonist activity toward opioid kappa receptor is needed, in a mammalian subject, when comprises administering to said subject a therapeutically effective amount of a compound according to claim 1 .
 11. A compound of the following formula:

wherein Ar^(2a) is phenyl, pyridyl or thienyl; X is hydrogen, halo or C₁-C₇ alkoxy; R¹ is hydrogen, optionally piotected hydroxy or C₁-C₄ alkyl; and R² and R³ are independently hydrogen or C₁-C₇ alkyl optionally substituted by hydroxy or halo.
 12. A compound according to claim 11 selected from 4-methylamino-N′-propylbenzamide; 5-N-methylamino-N′-propylpicolinamide; 2-chloro-4-methylamino-N′-propylbenzamide; 4-methylamino-N′-(2-(S)-hydroxypropyl)benzamide; 4-methylarino-N′-(2-(R)-hydroxypropyl)benzamide, 4-methylamino-N′-(2,2,3,3,3-pentafluoropropyl)benzamide; and 4-methylamino-N′-tert-amylbezamide.
 13. A compound selected from 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethanol; 2-(3-(S)-fluoropyrrolidin- 1-yl)-2-(R)-phenylethanol; 2-(R)-phenyl-2-(3 -pyrroline-1-yl)ethanol, 2-(3-(R)-fluoropyrnolidin-1-yl)-1-(S)-phenylethanol; 2-(3-(R)-fluoropyrrolidin-1-yl)-2-(R)-phenylethanol; 2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylethanol, 2-(3-(S)-fluoropyrrolidin-1-yl)-2-(S)-phenylethanol 2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethanol; and 2-(3-(S)-chloropyrrolidin-1-yl)-2-(R)-phenylethanol.
 14. A process for producing a compound of formula (I), which comprises reacting an amide compound of the formula (VId):

with an ethanol compound selected from compounds (Va), (Vb) and (Vc), and a mixture of compounds (Va) and (Vb):

in the absence or presence of a base in a reaction inert solevent. 